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  5. 全球精子库安全隐患与癌症遗传风险关联研究综述

全球精子库安全隐患与癌症遗传风险关联研究综述

深度研究匿名用户发表于 2025年12月21日 14:260阅读
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1. 全球精子库运作模式与潜在安全风险

1.1 精子库核心运作流程与质量控制标准

精子库的运作涉及一系列精细且标准化的流程，旨在确保所提供精子的质量和安全性。这些流程主要包括供体筛选、精液冷冻保存以及信息管理等核心环节。

供体筛选 是精子库运作的首要且至关重要的一步。这一阶段旨在选择生理和遗传健康的男性作为精子捐赠者。筛选内容通常包括：

  • 健康检查：捐赠者需进行全面的体格检查，评估其整体健康状况，排除传染病（如HIV、乙肝、丙肝、梅毒等）和遗传性疾病的风险 1。此外，还会进行心理评估，确保捐赠者具备捐赠能力。
  • 精液质量评估：对捐赠者的精液样本进行详细分析，包括精子浓度、活力、形态学以及冷冻复苏后的存活率。选择能够承受冷冻和解冻过程并保持较高活力的精子样本至关重要 2。
  • 家族史调查：详细询问捐赠者的家族病史，特别是遗传性疾病和慢性病史，以识别潜在的遗传风险。

冷冻保存技术 是精子库的核心技术环节，它确保精子在超低温环境下长期保存而不丧失其生物学活性。

  • 冷冻保存参数：精子通常在液氮中进行冷冻保存，温度可达-196°C 34。精确控制降温速率和冷冻介质的组成对于减少精子损伤至关重要 56。常用的冷冻保护剂，如甘油，能有效防止冰晶形成对精子细胞造成损害 5。
  • 复苏存活率保障：冷冻后的精子样本会在特定条件下进行复苏测试，以评估其在解冻后的活力、存活率和功能完整性 27。精子库通常会保证解冻样本中活性精子的数量和质量，以满足辅助生殖技术的需求 2。

信息管理 贯穿于精子库运作的始终，确保捐赠者信息的可追溯性和受赠家庭的安全性。

  • 供体遗传背景记录：详细记录捐赠者的所有健康检查结果、遗传检测数据以及家族病史，并建立完善的档案。这些信息对于后续评估遗传风险和提供遗传咨询至关重要。
  • 受赠家庭追踪：精子库会建立受赠家庭的档案，记录精子样本的使用情况和后代的健康状况。这种追踪机制有助于及时发现潜在的遗传问题，并为受赠家庭提供必要的支持和信息。在某些情况下，为保障安全性，精子库会向客户告知其所执行的筛查以及收集的捐赠者背景信息 2。

1.2 现有安全防控体系的主要漏洞

尽管全球精子库在运作中已建立了一套看似完善的筛选和管理流程，但当前的防控体系仍存在诸多不容忽视的漏洞，这些漏洞可能导致遗传风险的传播，尤其是在隐性遗传疾病和复杂疾病（如癌症）方面。

1. 筛查流程对隐性遗传疾病的覆盖盲区：

许多精子库主要依赖捐赠者的家族史调查和常规的遗传病检测来排除遗传风险89。然而，这种方法对于隐性遗传疾病存在显著的局限性。

  • 家族史的局限性：家族史调查往往只能识别已知的、有明显临床表现的遗传疾病。对于那些携带隐性致病基因的捐赠者，如果其家族中没有表现出该疾病，则无法通过家族史被发现810。例如，中国许多精子库仍主要依靠三代家族史评估来排除具有临床症状的遗传疾病，这导致许多隐性遗传风险在捐赠者资格审查前无法被检测到8。
  • 常规基因检测范围狭窄：传统的基因检测通常只针对少数常见的、高发病的遗传疾病，如地中海贫血、G6PD缺乏症等811。对于数量庞大且高度异质性的其他隐性遗传疾病，特别是与癌症相关的基因变异，现有筛查手段往往未能全面覆盖。一项对中国精子库的调查显示，虽然所有合格捐赠者都进行了核型分析，但只有26家精子库中的2家（7.7%）报告进行了全外显子组测序（WES），而基因检测的患者需求却在增加11。这意味着大多数精子库未能采用更全面的基因检测技术来识别潜在的隐性携带者。
  • 未纳入癌症相关基因检测：癌症通常被认为是多基因和环境因素共同作用的结果，但许多癌症类型具有明确的遗传易感性。然而，目前多数精子库的常规筛查并未将全面的癌症相关基因检测纳入标准流程。研究表明，即使是扩展性携带者筛查（ECS）面板也仅覆盖部分基因，且不同面板之间存在差异，未能完全捕捉到所有致病性突变1213。这意味着捐赠者可能携带与癌症风险增加相关的基因突变，但由于未进行特定检测而未能被发现，从而将这种风险传递给后代。例如，一项针对中国精子捐赠者的研究发现，通过全外显子测序，95.14%的捐赠者至少携带一个致病或可能致病的变异体，其中不乏常染色体隐性遗传、二基因隐性遗传和复杂遗传模式的变异14。这些发现强调了当前筛查的不足。

2. 跨代遗传风险评估缺失：

现有体系在评估遗传风险的跨代传递方面存在不足。

  • 复杂遗传模式的挑战：许多疾病，包括癌症，表现出复杂的遗传模式，涉及多个基因的协同作用以及基因与环境的相互作用。单一的基因检测或家族史调查难以全面评估这类复杂疾病的跨代传递风险10。
  • 晚发性疾病的漏检：一些遗传性疾病，如许多遗传性癌症综合征，其临床症状可能在中年甚至老年才出现。在年轻的精子捐赠者身上，即使携带致病基因，也可能在捐赠时未表现出任何疾病迹象，从而逃避筛查。

3. 供体健康信息动态更新机制缺陷：

精子捐赠者的健康状况并非一成不变，但现有精子库体系往往缺乏有效的动态更新机制。

  • 长期追踪不足：捐赠者在捐赠后，其健康状况可能会随着年龄增长而发生变化，例如可能被诊断出新的遗传性疾病或癌症。然而，精子库通常缺乏对捐赠者进行长期、持续的健康信息追踪和更新的机制10。
  • 信息披露的滞后性：即使捐赠者后续被诊断出与遗传风险相关的问题，精子库也可能无法及时获取这些信息，或者在获取后未能及时向受赠家庭披露，从而使受赠家庭面临未知的风险。这涉及伦理和法律问题。
  • 缺乏统一标准：全球范围内，精子库在捐赠者健康信息管理和更新方面缺乏统一的指导方针和强制性要求，使得各机构在实践中存在显著差异9。这增加了潜在的遗传风险传递的可能性。一项批评美国人工授精行业的报告指出，由于缺乏适当的筛查方法来避免将遗传疾病传染给通过人工授精出生的儿童，人工授精固有的危险性得以暴露15。这凸显了行业监管和标准化的必要性。

2. 精子库关联癌症事件的典型案例剖析

2.1 爆雷事件的具体表现与家庭影响

近年来，全球精子库偶发的安全事件，特别是涉及遗传风险导致的后代患癌案例，给相关家庭带来了沉重的打击和深远的社会影响。这些“爆雷”事件不仅暴露了现有精子库筛选机制的漏洞，也引发了公众对辅助生殖技术伦理与安全的广泛关注。

典型案例中，受影响家庭的后代往往在儿童或青少年时期被诊断出患有严重癌症，如白血病、淋巴瘤、视网膜母细胞瘤、神经纤维瘤病或特定类型的实体肿瘤。这些癌症的发病年龄通常远低于散发性癌症的平均发病年龄，且其家族中此前并无相关病史，这使得受赠家庭在发现病情后，往往难以理解其病因。例如，一些案例报告指出，某些精子捐赠者本身可能携带BRCA1/2等癌症易感基因，或存在未被披露的癌症家族史，这些信息在捐赠时未能被有效识别，最终导致其生物学后代罹患相关癌症。还有一些案例可能涉及捐赠者携带罕见的遗传性疾病基因，这些疾病以增加癌症风险为主要临床表现，如Li-Fraumeni综合征等。

这些癌症事件对家庭造成的影响是多方面的，且具有毁灭性：

  • 癌症类型与发病年龄分布：受影响的后代被诊断出的癌症类型涵盖了从血液系统恶性肿瘤到各种实体瘤。例如，有报道称，一些儿童被诊断出罹患急性淋巴细胞白血病或急性髓性白血病，这些白血病在儿童期具有较高的遗传倾向。另外，视网膜母细胞瘤、神经母细胞瘤以及某些遗传性结直肠癌等也曾在精子库相关案例中被提及。这些癌症的发病年龄通常集中在儿童期或青少年期，使得年轻的生命面临巨大的健康威胁。
  • 心理与精神负担：对于受赠家庭而言，养育一个患有重疾的儿童本身就是巨大的挑战。当得知孩子的癌症可能源于精子捐赠者的遗传缺陷时，家庭成员会经历极度的震惊、愤怒、内疚和无助。他们可能感到被欺骗和背叛，对精子库的信任彻底瓦解。这种心理创伤不仅影响父母，也对患病儿童的兄弟姐妹造成心理阴影。长期的治疗过程、预后的不确定性以及对未来健康的担忧，都使得家庭长期处于高压状态。
  • 经济负担：癌症的诊断和治疗是一个漫长且昂贵的过程，包括手术、化疗、放疗、靶向治疗、免疫治疗以及长期的康复和随访。这些高昂的医疗费用往往超出普通家庭的承受能力，导致家庭陷入严重的经济困境，甚至倾家荡产。此外，父母为了照顾患病的孩子，可能需要放弃工作或减少工作时间，进一步加剧了经济压力。
  • 社会伦理与法律困境：这些事件还引发了复杂的社会伦理和法律问题。受赠家庭可能会对精子库提起诉讼，要求赔偿医疗费用和精神损失。在美国，精子在产品责任法之下被视为一种产品，这意味着精子库可能对其提供的精子的质量和安全性承担法律责任 16。然而，如何界定精子库的责任范围、如何评估遗传风险的披露程度以及如何在捐赠者隐私与受赠家庭知情权之间取得平衡，都成为亟待解决的难题。这些事件也促使人们重新审视精子捐赠的伦理义务，特别是捐赠者在得知自身健康状况变化后，是否有义务向精子库披露其更新的遗传信息 17。
  • 对捐赠制度的信任危机：此类事件的曝光严重损害了公众对精子库行业的信任。许多潜在的受赠家庭可能会对辅助生殖技术的安全性产生疑虑，从而影响他们选择通过精子捐赠实现生育的意愿。同时，这也可能使得一部分潜在的精子捐赠者因对未来法律责任的担忧或对个人信息披露的顾虑而却步，对精子库的运作和优质精源的获取造成负面影响。

2.2 事件中遗传风险的传播路径

精子库关联癌症事件中遗传风险的传播并非偶然，其背后往往隐藏着现有筛选机制的疏漏和遗传变异传递的复杂性。理解这些传播路径对于改进精子库的安全防控体系至关重要。

1. 问题供体的筛查疏漏点：

这些事件的发生，核心在于问题供体在筛选阶段未能被有效识别，主要体现在以下几个方面：

  • 未披露或隐瞒癌症家族史：部分捐赠者可能在提交申请时，未能全面、准确地披露其家族中的癌症病史，甚至有意隐瞒。例如，有些捐赠者可能认为家族中“远亲”的癌症史与自己无关，或者不理解某些疾病的遗传关联性，导致其在健康问卷中未能提供关键信息 18。由于精子库主要依赖自我报告和家族史调查来评估遗传风险，这种信息的不完整或不准确性直接导致了高风险个体的漏检。研究表明，家族史在多种癌症风险评估中扮演重要角色，如睾丸癌、前列腺癌和乳腺癌的家族史都与患病风险显著相关 18。若这些信息被遗漏，则精子库无法有效识别潜在风险。
  • 基因检测未覆盖高风险位点：即使精子库实施了基因检测，其检测范围也往往存在局限性。多数精子库的常规基因检测通常聚焦于少数常见隐性遗传病（如囊性纤维化），而对与癌症相关的遗传易感基因（如BRCA1/2、TP53、APC等）的全面检测则尚未普及 1319。这意味着捐赠者可能携带已知与高癌症风险相关的基因突变，但由于这些突变未包含在标准的检测面板中，从而导致其顺利通过筛查。例如，某些商业基因筛查面板虽然能检测到一些严重的儿科疾病突变，但不同面板之间的基因覆盖范围差异显著，且“绝大多数致病性突变组合仍未被商业携带者筛查面板检测到” 13。一项研究发现，对囊性纤维化检测呈阴性的捐赠者，通过更全面的下一代测序分析，几乎所有捐赠者都被发现携带一种或多种与严重单基因儿科疾病相关的突变 13。这表明现有筛查的广度与深度不足。
  • 多基因和复杂遗传模式的挑战：许多癌症具有多基因遗传特性，即其风险由多个基因共同作用决定，并受环境因素影响。现有筛查方法很难评估这类复杂遗传风险。例如，多基因风险评分（PRS）虽然在预测某些复杂疾病方面显示出潜力，但尚未广泛应用于精子库的常规筛查中。
  • 晚发性遗传病的识别不足：部分遗传性癌症综合征，如遗传性非息肉病性结直肠癌（Lynch综合征）或遗传性乳腺卵巢癌综合征，其临床症状通常在中年以后才显现。年轻的精子捐赠者即使携带致病基因，在捐赠时也可能无任何临床表现，导致无法通过常规体检被发现。
  • 对拷贝数变异（CNVs）的忽视：除了点突变，拷贝数变异也是重要的遗传变异类型，与多种疾病的发生发展相关。然而，传统精子库筛查可能未能全面评估捐赠者的CNVs情况，从而忽略了潜在的致病性CNVs。

2. 遗传变异通过精子传递至后代的具体机制：

遗传变异通过精子传递给后代的机制，遵循孟德尔遗传定律，但其具体过程因变异类型而异。

  • 单基因突变的直接传递：如果捐赠者携带一个与癌症风险相关的显性致病基因突变（例如BRCA1/2的种系突变），那么其后代有50%的概率遗传到这个突变。即使是隐性基因突变，如果受赠者也恰好是同一隐性基因的携带者，则后代有25%的概率患病。精子细胞携带捐赠者的一半遗传物质，其中就包括所有体细胞和生殖细胞中存在的基因组DNA。当携带致病突变的精子与卵子结合形成受精卵时，该突变便直接整合到受精卵的基因组中，从而传递给后代。这种垂直传递方式已被广泛研究，如Preimplantation Genetic Testing for Monogenic defect (PGT-M)技术即是为防止已知单基因疾病垂直传递而开发的 20。
  • 染色体异常的传递：除了基因点突变，捐赠者如果存在染色体结构或数量异常（如易位、缺失、重复等），这些异常也可能通过精子传递给后代。某些染色体异常与特定癌症的风险增加有关。例如，基因组中的拷贝数变异（CNVs）在传递过程中有近80%是遗传自父母的 21。
  • 表观遗传修饰的影响：除了基因序列本身的变异，精子中携带的表观遗传信息（如DNA甲基化、组蛋白修饰等）也可能对后代的基因表达和疾病风险产生影响。虽然这方面的研究尚处于早期阶段，但已有证据表明，父系来源的表观遗传信息可能与某些疾病的发生有关。例如，某些与配子形成、表观遗传调控相关的途径可能涉及遗传传递扭曲 22。
  • “新发”突变（De Novo Mutations）：尽管较少见，但在精子形成过程中也可能发生新的基因突变，即新发突变。这些突变虽然并非继承自捐赠者体细胞，但一旦发生在生殖细胞中并传递给后代，同样可能导致疾病。然而，大多数问题案例仍指向捐赠者本身携带的遗传变异。

总之，精子库关联癌症事件中遗传风险的传播路径，暴露出当前供体筛查在深度和广度上的不足，尤其是在复杂遗传疾病和晚发性遗传病方面的识别能力有待加强。未来，需要更全面的基因检测、更严格的信息披露机制以及对捐赠者长期健康的动态追踪，来有效阻断这些风险的传递。

3. 癌症遗传因素的科学基础与占比研究

3.1 癌症遗传易感性的分子机制

癌症的发生是一个复杂的过程，涉及多种分子机制的失调，其中遗传因素扮演着不可忽视的角色。理解这些分子机制是评估和预防癌症遗传风险的基础。癌症的遗传易感性主要通过单基因突变、多基因变异以及表观遗传修饰等多种途径影响个体的患病风险。

1. 单基因突变：

某些癌症与特定基因的种系突变（Germline Mutations）密切相关，这些突变可直接遗传给后代，显著增加患癌风险。

  • BRCA1/2突变：乳腺癌和卵巢癌家族性聚集的一个重要原因就是BRCA1和BRCA2基因的种系突变。携带这些突变的人群患乳腺癌和卵巢癌的风险显著高于一般人群。这类基因在DNA损伤修复中发挥关键作用，其功能缺失会导致基因组不稳定，从而增加癌症风险。
  • TP53突变：Li-Fraumeni综合征是由TP53基因种系突变引起的罕见遗传性疾病，患者在儿童和青少年时期易患多种恶性肿瘤，包括肉瘤、乳腺癌、白血病和脑肿瘤等。TP53被称为“基因组的守护者”，在细胞周期调控、DNA修复和细胞凋亡中起核心作用。
  • APC基因突变：家族性腺瘤性息肉病（FAP）是由APC基因种系突变引起的，患者结肠和直肠内会形成数百甚至数千个腺瘤性息肉，如果不及时治疗，几乎100%会发展为结直肠癌。
  • MLH1, MSH2, MSH6, PMS2突变：这些基因的种系突变与Lynch综合征（也称为遗传性非息肉病性结直肠癌, HNPCC）相关，显著增加结直肠癌、子宫内膜癌及其他多种癌症的风险。这些基因编码的蛋白参与DNA错配修复，功能缺失会导致微卫星不稳定，进而驱动肿瘤发生。
  • MUTYH基因突变：结直肠癌的遗传易感性还包括MUTYH基因的致病性编码变异，如rs36053993（G396D），该变异与早发性结直肠癌风险显著相关23。

2. 多基因变异与多基因风险评分 (Polygenic Risk Scores, PRS)：

与单基因突变导致的高外显率癌症不同，大多数癌症的遗传易感性是由多个常见基因变异（通常是单核苷酸多态性，SNPs）的累积效应决定的，这些基因变异单独作用时影响较小，但共同作用时可显著改变患癌风险。

  • GWAS研究的贡献：全基因组关联研究（Genome-Wide Association Studies, GWAS）通过扫描全基因组，识别出大量与癌症风险相关的常见遗传变异24。例如，在结直肠癌中，GWAS已识别出多个风险位点，通过整合血浆蛋白质组与基因组数据，能够识别出与结直肠癌风险相关的蛋白质生物标志物，这有助于深入理解其病因并发现潜在的治疗靶点25。
  • 多基因风险评分 (PRS)：基于GWAS数据，研究人员开发了多基因风险评分（PRS），通过综合个体携带的多个风险变异来量化其患特定癌症的遗传倾向。PRS已在前列腺癌26、结直肠癌27、膀胱癌24等多种癌症中显示出预测潜力。例如，一项研究利用130个与前列腺癌风险增加相关的常见种系变异构建了PRS，发现PRS得分在90%以上的个体中，前列腺癌的检出率显著高于PSA或MRI筛查所能识别的比例26。另有研究表明，结合PRS与临床风险因素，可以更好地对结直肠癌患者进行风险分层，甚至预测个性化的起始筛查年龄2728。PRS还能用于评估不同人群的癌症风险，例如，整合东亚和欧洲人群的GWAS数据构建的PRS，在不同族裔中均能有效评估结直肠癌风险29。

3. 表观遗传变异：

除了DNA序列本身的改变，基因表达的调控也会受到表观遗传修饰的影响。这些修饰不改变DNA序列，但可以影响基因的开启或关闭，在癌症的发生发展中发挥重要作用303132。

  • DNA甲基化：DNA甲基化是指DNA分子中的胞嘧啶碱基上添加甲基基团。在癌细胞中，常常观察到基因组整体低甲基化和特定抑癌基因启动子区域高甲基化，导致抑癌基因沉默，促进肿瘤生长3334。
  • 组蛋白修饰：组蛋白是DNA缠绕的蛋白质，其化学修饰（如乙酰化、甲基化、磷酸化等）会改变染色质结构，从而影响基因表达。癌细胞中组蛋白修饰模式的异常已被广泛研究，并被认为是癌症治疗的潜在靶点32。例如，食管鳞状细胞癌的基因组分析显示，多个重要的组蛋白调节基因（如MLL2, ASH1L, MLL3, SETD1B, CREBBP和EP300）常发生改变35。
  • 核小体重塑：核小体是染色质的基本结构单位。核小体定位和重塑的异常也会影响基因的可及性，进而影响基因表达，在癌症中也观察到这类机制的失调30。
  • RNA介导的调控：非编码RNA，特别是微小RNA（miRNA），在基因表达调控中发挥重要作用。在癌症中，miRNA的异常表达可以作为致癌基因或抑癌基因，影响细胞增殖、分化、凋亡等过程。例如，在食管鳞状细胞癌中，MIR548K被鉴定为一个新型致癌基因，可增强ESCC细胞的恶性表型35。

这些遗传和表观遗传机制并非独立运作，而是相互作用，共同决定了个体的癌症风险。例如，基因突变可以影响表观遗传调节因子的功能，而表观遗传修饰也可能影响基因组的稳定性，从而促进突变的发生31。对这些分子机制的深入理解，为精子库进行更精准的遗传风险评估和筛查提供了理论基础。

3.2 遗传因素在癌症发生中的贡献度评估

评估遗传因素在癌症发生中的贡献度是一个复杂的问题，因为癌症往往是遗传、环境和生活方式等多种因素交互作用的结果 3637。尽管如此，通过流行病学数据、双生子研究和家族史分析，科学家们已对不同癌症类型中遗传因素的占比进行了量化评估，并探讨了环境-遗传交互作用的影响。

1. 流行病学数据与遗传因素占比：

流行病学研究表明，约有5%到15%的散发性癌症（即非家族性聚集的癌症）与遗传因素有关 38。这意味着在大多数癌症病例中，环境和生活方式因素可能发挥了更主导的作用。然而，对于某些特定癌症类型，遗传因素的贡献显著更高。

  • 家族性癌症：约5%-10%的癌症被认为是家族性或遗传性癌症，这些病例通常由高外显率的单基因突变引起，如BRCA1/2突变与乳腺癌和卵巢癌 383940、APC突变与结直肠癌等。在这些家族性癌症中，遗传因素的贡献接近100%。例如，视网膜母细胞瘤（Retinoblastoma）几乎所有病例都与RB1基因突变相关，无论遗传性或散发性，均需RB1基因的两个等位基因突变才致病 41。
  • 散发性癌症中的遗传成分：即使在没有明确家族史的散发性癌症中，遗传易感性基因的变异也可能增加患病风险。例如，胰腺癌患者中，即使没有明显的家族史，也有3.9%的患者携带致病性种系突变，其中BRCA2、ATM等基因最为常见 42。另一项针对中国胰腺癌患者的研究也发现，6.2%的PDAC患者携带致病性变异，其中BRCA2和PALB2与胰腺癌风险显著相关 43。对于卵巢癌，最常见的遗传因素包括MTHFR C677T、BSML rs1544410和Fokl rs2228570等基因多态性，它们显著增加卵巢癌风险 44。对于乳腺癌，约5-10%的病例归因于遗传易感性，其中BRCA1和BRCA2基因的突变是迄今为止最著名的遗传因素 39。在膀胱癌中，尽管吸烟和职业暴露是主要风险因素，但基因-环境交互作用的重要性也日益凸显 45。

2. 双生子研究的量化证据：

双生子研究是评估遗传因素和环境因素相对贡献的有力工具，因为同卵双生子具有相同的遗传背景，而异卵双生子平均共享50%的基因。通过比较同卵双生子和异卵双生子在癌症发病上的一致性，可以推断遗传因素的贡献度。

  • 瑞典、丹麦和芬兰的双生子队列研究：一项对来自瑞典、丹麦和芬兰的44,788对双生子进行的大规模研究发现，在大多数癌症类型中，遗传因素对散发性癌症的易感性贡献较小，这表明环境因素在引起散发性癌症中扮演着主要角色 46。然而，该研究也指出，对于某些特定癌症，遗传力（heritability）效应显著：
    • 前列腺癌：遗传因素贡献度高达42%（95%置信区间，29%至50%）。
    • 结直肠癌：遗传因素贡献度为35%（95%置信区间，10%至48%）。
    • 乳腺癌：遗传因素贡献度为27%（95%置信区间，4%至41%）。
    • 对于胃癌和肺癌，研究发现受影响个体双生子罹患癌症的风险有所增加 46。
  • 单合子双生子在表观遗传学研究中的应用：单合子双生子（同卵双生子）在表观基因组学研究中具有巨大潜力，因为它们共享相同的遗传背景，这使得研究人员能够在没有基因混杂影响的情况下分析表观遗传变异。通过比较患癌和未患癌的同卵双生子，可以识别可能受环境影响的易感基因位点，进而发现癌症检测和风险评估的可靠表观遗传标记 47。

3. 环境-遗传交互作用的影响：

需要强调的是，遗传因素和环境因素并非独立作用，而是紧密交互，共同影响癌症的发生发展。这种交互作用可以体现在多个层面：

  • 基因对环境暴露的响应：个体遗传背景决定了其对特定环境致癌物（如烟草、空气污染物、饮食）的敏感性。例如，某些基因多态性可能影响个体对致癌物的代谢能力或DNA损伤修复效率，从而改变其在相同暴露水平下的患癌风险 45。有研究表明，环境空气污染与结直肠癌风险和生存率增加相关，特别是对于体力活动不足和吸烟者，这种关联更为显著 48。
  • 环境诱导的表观遗传改变：环境因素可以通过改变DNA甲基化、组蛋白修饰等表观遗传标记，进而影响基因表达，增加癌症风险 3647。例如，组织损伤与KRAS癌基因突变结合，可显著加速胰腺癌的发生，这其中涉及独特的染色质状态形成和表观遗传重编程 36。空气污染也被发现可能通过表观遗传修饰（如DNA甲基化）来介导其对结直肠癌的致病作用 48。
  • 生活方式因素：饮食习惯、体力活动、吸烟、饮酒等生活方式因素与遗传易感性结合，可以显著改变癌症风险。例如，吸烟是膀胱癌的主要风险因素，但不同个体对烟草致癌物的敏感性可能因遗传背景而异 45。

综上所述，虽然遗传因素在大部分散发性癌症中的贡献相对较小，但在某些特定癌症类型中扮演着关键角色，尤其是在家族性癌症和早发性癌症中。双生子研究提供了量化遗传力的直接证据。同时，深入理解环境与遗传因素的复杂交互作用，对于全面评估癌症风险和制定精准预防策略具有重要意义。精子库在评估供体健康时，必须将这些复杂的遗传易感性及其与环境的交互作用纳入考量，以更全面地识别和规避潜在的癌症遗传风险。

4. 精子库中癌症遗传风险的评估与防控技术

4.1 现有遗传风险评估工具的局限性

在精子库的运作中，准确评估供体的癌症遗传风险至关重要。然而，目前广泛采用的遗传风险评估工具，包括传统的家族史调查和基础基因检测，存在显著的局限性，导致癌症相关遗传变异的漏检率较高。这些局限性促使行业寻求更先进的检测技术，如新一代测序（Next-Generation Sequencing, NGS）技术，以提升筛查的全面性和准确性。

1. 传统家族史调查与基础基因检测的局限性：

  • 依赖自我报告的准确性与完整性：家族史调查主要依赖于捐赠者对自身及亲属健康信息的记忆和报告。这种方式极易受到捐赠者主观判断、认知偏差或信息获取能力限制的影响。例如，捐赠者可能对远亲的病史不清楚，或因隐私顾虑而选择性披露信息 4950。有研究显示，通过遗传咨询师进行的遗传风险评估比单纯依赖自我报告的申请表能提供更全面的个人和家族病史信息，且有高达84%的申请者在遗传风险评估中报告了新的健康信息 50。这种信息不对称性导致了潜在癌症家族史的遗漏。

  • 对隐性遗传病和晚发性疾病的识别不足：许多遗传性癌症（如一些由BRCA1/2突变引起的乳腺癌/卵巢癌、Li-Fraumeni综合征）可能直到中年或老年才发病。年轻的精子捐赠者即使携带这些致病基因，在捐赠时可能尚未表现出症状，且其家族成员可能也未发病，导致家族史无法揭示潜在风险。此外，对于携带隐性致病基因的捐赠者，若其家族中没有受影响的个体，则通过家族史无法识别其携带者状态。

  • 基因检测范围的局限性：传统的基础基因检测通常包括染色体核型分析和针对少数高发疾病的基因检测，例如囊性纤维化、脊髓性肌肉萎缩症等。

    • 染色体核型分析：虽然能检测染色体数目和结构上的较大变异，如唐氏综合征（21三体）、特纳综合征（XO）等，但对于微小缺失/重复、基因点突变以及平衡易位等精细的遗传变异则无法识别 51。例如，染色体14q32区域的微缺失可导致Kagami-Ogata综合征和Temple综合征，这种微小变异是传统核型分析难以发现的 51。睾丸癌患者的精子染色体核型分析显示，在化疗前后，精子染色体异常的频率（包括数量和结构异常）并未显著增加 5253，但这些研究主要关注宏观染色体变异，而非基因水平的细微突变。
    • 针对特定疾病的基因检测：现有精子库常采用的基因检测面板，即便涵盖了部分常见的隐性遗传疾病，也往往未能全面覆盖与癌症风险相关的所有已知基因突变。不同检测面板之间基因覆盖的差异，使得一些致病性突变组合可能未被商业携带者筛查面板检测到。例如，虽然Turner综合征与特定癌症风险增加有关，但这种风险的遗传基础复杂，并非简单的单基因突变即可解释 54。

  • 无法识别从头突变（De Novo Mutations）：传统方法无法识别在精子形成过程中新发生的致病性突变，而这些突变也可能传递给后代并导致疾病。

2. 新一代测序（WES/WGS）在精子库供体筛查中的应用潜力：

为了克服传统评估工具的局限性，新一代测序技术，特别是全外显子组测序（Whole Exome Sequencing, WES）和全基因组测序（Whole Genome Sequencing, WGS），为精子库供体筛查提供了更全面、更深入的解决方案。

  • WES/WGS的全面性：
    • 全外显子组测序（WES）：主要测序蛋白质编码区（外显子），这部分基因组虽然只占总基因组的约1%-2%，但包含了约85%的已知致病突变。WES可以一次性检测数千个基因的突变，包括与癌症易感性相关的已知基因和潜在基因。
    • 全基因组测序（WGS）：则测序整个基因组，包括外显子、内含子以及基因间区域。WGS能够检测到所有类型的遗传变异，包括单核苷酸变异（SNVs）、插入/缺失（Indels）、拷贝数变异（CNVs）以及染色体重排。这对于识别那些位于非编码区但对基因表达和癌症风险有重要影响的变异尤为关键。
  • 提高癌症相关基因变异的检出率：WES/WGS能够显著提高对癌症相关基因变异的检出率，包括显性、隐性以及一些复杂遗传模式的致病变异。通过对捐赠者进行WES/WGS，可以识别其是否携带高风险的癌症易感基因突变（如BRCA1/2、TP53、MLH1/MSH2等），从而避免将这些风险传递给后代。
  • 发现新发突变和罕见变异：WES/WGS不仅能检测已知基因的变异，还有潜力发现之前未知的或罕见的致病变异，包括从头突变。这对于评估捐赠者的“新发”癌症风险具有重要意义。
  • 辅助诊断和遗传咨询：通过WES/WGS获得的详细遗传信息，可以为捐赠者和受赠家庭提供更精准的遗传咨询。例如，如果发现捐赠者携带某些癌症易感基因，遗传咨询师可以评估其遗传风险，并为受赠家庭提供个性化的建议，包括后续的筛查策略和预防措施。
  • 挑战与限制：尽管WES/WGS潜力巨大，但也面临挑战。
    • 数据解读的复杂性：WES/WGS产生海量数据，其中包含大量临床意义未知的变异（Variants of Unknown Significance, VUS），这给解读和临床应用带来了困难。需要专业的生物信息学分析和遗传学解读能力。
    • 成本与可及性：尽管测序成本不断下降，但WES/WGS相对于传统检测仍是昂贵的。其在精子库中的普及，需要权衡成本效益和伦理可接受性。
    • 偶然发现（Incidental Findings）：测序可能会偶然发现与捐赠者本人或其家族健康相关的非目标疾病信息，这引发了关于信息披露的伦理和法律问题。
    • 动态性：遗传风险并非一成不变，新的研究不断发现基因与疾病的新关联。测序结果的定期再分析和更新，以及对捐赠者未来健康状况的长期追踪，是确保其持续有效性的关键。

综上所述，现有的遗传风险评估工具在精子库供体筛查中存在明显局限，尤其是对癌症相关遗传变异的漏检率较高。引入WES/WGS等新一代测序技术，有望显著提升筛查的全面性和准确性，但同时也需解决数据解读、成本、伦理等方面的挑战，以实现更安全、更负责任的辅助生殖服务。

4.2 前瞻性防控策略的技术升级

面对现有遗传风险评估工具的局限性，精子库需要积极采纳和开发前瞻性的防控策略，通过技术升级来更全面、精准地评估和管理癌症遗传风险。这些策略包括整合多组学数据、应用人工智能算法以及优化冷冻精子DNA损伤检测技术。

1. 基于多组学（基因组、转录组、蛋白组）的供体遗传风险综合评估模型：

传统的基因检测主要关注基因组层面的变异，而多组学技术则能够从更广泛的生物学层面揭示个体健康状况和疾病风险。将基因组学、转录组学和蛋白质组学数据相结合，可以构建更全面的供体遗传风险评估模型。

  • 基因组学（Genomics）：如前所述，全外显子组测序（WES）和全基因组测序（WGS）是基因组学在精子库筛查中的核心应用。它们能够检测捐赠者是否携带与疾病相关的致病性或可能致病性变异，包括单核苷酸变异（SNVs）、插入/缺失（Indels）、拷贝数变异（CNVs）以及染色体重排。通过分析这些变异，可以评估捐赠者罹患遗传性疾病的风险，或其将特定疾病易感基因传递给后代的风险 1455。例如，对中国精子捐赠者的临床外显子组测序（CES）研究发现，95.14%的捐赠者至少携带一个致病或可能致病的变异，平均每个捐赠者携带3.53个隐性遗传缺陷，这些发现支持CES在捐赠者筛选中的应用，可以识别携带基因条件并排除具有显性遗传障碍史的捐赠者 14。
  • 转录组学（Transcriptomics）：通过分析精子或供体体细胞的基因表达谱，可以发现与疾病发生发展相关的基因表达异常。例如，某些基因的异常高表达或低表达可能预示着细胞代谢途径的改变，这可能与肿瘤的早期发生有关。然而，精子本身的转录组特征复杂且受多种因素影响，其在癌症风险评估中的直接应用仍需深入研究。
  • 蛋白质组学（Proteomics）：蛋白质是生命活动的主要执行者，其表达水平和修饰状态的变化与疾病密切相关。通过蛋白质组学技术分析精浆或精子蛋白，可以识别与精子质量、遗传完整性或潜在疾病风险相关的生物标志物。例如，研究发现冷冻保存过程可能诱导精子中氧化应激，导致过氧化物酶（PRDX5和PRDX6）等蛋白质发生易位和寡聚化，这些变化可能反映了精子对损伤的适应性反应 56。虽然这些研究主要集中在精子质量方面，但未来有望扩展到识别与癌症相关的蛋白质标志物。
  • 多组学整合优势：将基因组学提供的潜在遗传风险，与转录组学和蛋白质组学提供的基因表达和功能层面信息相结合，能够构建一个更为动态和全面的遗传风险评估视图。例如，即使基因组中存在易感基因变异，如果其在特定组织或环境下并未导致基因表达异常或蛋白质功能缺陷，其致病性可能较低。反之，基因组、转录组和蛋白质组层面的多重异常，则可能提示更高的疾病风险。

2. 结合AI算法预测癌症遗传风险的可行性：

随着多组学数据的爆炸式增长，人工分析已难以应对。人工智能（AI）和机器学习（ML）算法在处理高维复杂数据、识别模式和预测风险方面展现出强大潜力，为精子库中的癌症遗传风险预测提供了新途径。

  • 风险预测模型：AI算法可以整合来自基因组测序、家族史、临床表型甚至生活方式数据等多种来源的信息，构建复杂的风险预测模型。这些模型能够识别出传统方法难以发现的、基因组中微弱但协同作用的风险信号。例如，多基因风险评分（Polygenic Risk Scores, PRS）便是利用大量常见遗传变异（SNPs）的累积效应来量化个体患复杂疾病（包括癌症）风险的工具 57。
  • 变异解读与分类：WES/WGS会产生大量变异数据，其中很多是临床意义不明的变异（VUS）。AI算法可以通过学习已知致病变异的特征，对VUS进行分类和优先级排序，从而辅助遗传学家进行决策，减少漏报和误报。
  • 个性化风险评估：基于AI的风险评估可以提供高度个性化的风险预测，不仅能告知个体患某种疾病的总体风险，还能指出哪些基因、哪些通路可能对其风险贡献最大。这对于精子库向受赠家庭提供遗传咨询，并制定个体化的风险管理策略具有重要意义。
  • 挑战：尽管AI潜力巨大，但其在精子库中的应用仍面临挑战：
    • 数据质量与规模：AI模型的建立需要高质量、大规模的训练数据，包括大量携带和未携带疾病易感基因的捐赠者数据，以及其后代的长期健康追踪数据。目前，精子库可能难以提供如此全面的数据集。
    • 模型可解释性：深度学习等复杂AI模型通常被认为是“黑箱”，其决策过程难以解释。在临床应用中，尤其是在涉及遗传风险这种高度敏感的领域，模型的可解释性至关重要，以便医生和患者理解其预测结果。
    • 伦理与隐私：使用AI处理和分析捐赠者的敏感遗传数据，需要严格遵守数据隐私保护法规，并解决由此引发的伦理问题。

3. 冷冻精子中DNA损伤检测技术的优化方向：

精子冷冻保存过程可能导致DNA损伤，而受损DNA的精子即使能够受精，也可能影响胚胎发育，增加后代疾病风险。因此，优化冷冻精子中DNA损伤检测技术，对于评估精子质量和遗传安全性至关重要。

  • 高灵敏度与特异性生物传感器：传统的精子DNA损伤检测方法（如SCSA）存在局限性。新的荧光酶基生物传感器，利用末端脱氧核苷酸转移酶（TdT）和内切酶IV，可以更灵敏、准确地检测冷冻保存精子中的DNA断裂点 58。另一项研究提出了基于TdT/Cas12a的生物传感器，其灵敏度极高（可检测低至0.001 nM的DNA断裂），且具有分子级别的分辨率，能够精确量化和定位DNA断裂点 59。这些创新技术远优于传统方法，能够提供更详细和准确的评估。
  • 检测不同类型DNA损伤：DNA损伤不仅包括断裂，还包括氧化损伤、碱基修饰等。未来的技术应能够全面检测不同类型的DNA损伤。例如，氧化应激是冷冻保存过程中导致DNA损伤的重要因素 56，因此，能够特异性检测氧化损伤的生物标志物或技术将具有重要价值。
  • 实时与无损检测：理想的DNA损伤检测技术应能实现对精子的实时、无损评估，从而在不影响精子活力的前提下筛选出高质量的精子。目前，大多数检测方法仍需要在精子处理后进行，未来需开发更先进的在体（in situ）或非侵入性检测方法。
  • 与辅助生殖技术的整合：将DNA损伤检测结果与辅助生殖技术（ART）的临床结局相结合，可以验证检测方法的预测价值，并指导临床选择最佳的精子样本。例如，通过评估精子DNA断裂点的平均数量，发现精子玻璃化冷冻对精子断裂点的影响最小，这为优化精子保存技术提供了新方法 60。

通过多组学整合、AI驱动的风险预测以及先进的DNA损伤检测技术，精子库有望建立起更为严密和高效的癌症遗传风险防控体系，从而显著降低后代罹患遗传性疾病的风险，提升辅助生殖技术的安全性和成功率。

5. 伦理争议与管理体系的优化路径

5.1 供体-受赠者信息披露的伦理困境

精子库在运作过程中，核心的伦理困境之一在于如何平衡供体（捐赠者）的遗传信息隐私权与受赠家庭的知情权。随着基因检测技术的发展和癌症遗传风险的日益凸显，这一困境变得尤为突出，对“义务性信息披露”的伦理边界及其在国际上的实践差异提出了严峻挑战。

1. 供体遗传信息隐私权与受赠家庭知情权的冲突：

  • 供体隐私权：精子捐赠者通常希望其个人信息，特别是敏感的遗传健康信息，能够得到严格保护。这种隐私权源于个人对其身体和个人信息的自主控制权，以及避免潜在社会歧视或身份暴露的意愿 6162。许多捐赠者选择匿名捐赠，正是为了避免与后代或受赠家庭建立关系，从而保护自己的生活不被打扰 6163。当捐赠者被诊断出罹患遗传性癌症或发现携带相关基因突变时，其可能不愿将这些信息披露给精子库，更不愿直接或间接告知受赠家庭，担心可能面临法律责任、社会压力或个人生活受到干扰。
  • 受赠家庭知情权：受赠家庭，尤其是当其后代被诊断出患有遗传性疾病或癌症时，具有强烈的知情权，希望了解供体的遗传背景，以便更好地理解孩子的病情、评估未来风险、寻求合适的治疗方案或进行遗传咨询 6465。这种知情权不仅关乎孩子的健康福祉，也涉及家庭对未来生育计划的决策。此外，一些观点认为，子女有权了解自己的遗传起源，这有助于其身份认同和心理健康发展 6667。如果供体信息能够提供重要的医疗信息，尽管可能性很小，但这有助于受赠家庭决定是否告知以前的受赠者和/或阻止剩余样本的使用 68。

这种权利之间的冲突在实践中表现为：精子库在收到供体健康信息更新时，是否以及如何告知受赠家庭。如果精子库选择不披露，可能侵犯受赠家庭的知情权和后代的健康权；如果选择披露，则可能侵犯供体的隐私权，甚至违反当初签署的匿名捐赠协议，对精子库的公信力造成损害。

2. 以癌症遗传风险为例分析“义务性信息披露”的伦理边界：

当精子捐赠者被诊断出或被发现携带与高风险癌症相关的遗传变异时，信息披露的伦理边界变得尤为复杂。

  • 披露的道德义务：从受赠家庭和后代的角度来看，如果供体的遗传信息对后代的健康具有重大且直接的影响（例如，携带高外显率的癌症易感基因突变），精子库似乎负有道德义务进行披露。这种义务通常基于“不伤害原则”和“受益原则”，即尽量避免伤害和促进福祉。
  • “重大”信息的界定：然而，何谓“重大”信息并非一成不变。例如，一个微小的遗传风险是否需要披露？一个在捐赠者晚年才发病的遗传性疾病，是否需要追溯披露给年轻的后代？这些问题需要精细的判断。一般来说，如果信息能够直接影响到受赠家庭的医疗决策（如定期筛查、预防性手术），或者对后代的健康有显著的负面影响，则更有可能被视为“重大”信息。
  • 披露方式的考量：即使决定披露，披露的方式也充满伦理挑战。直接告知受赠家庭供体的具体诊断可能会暴露供体身份，引发不必要的社会和法律问题。间接披露（如通过遗传咨询师提供匿名化的风险信息）可能是一种折衷方案，但其有效性取决于信息的具体性和受赠家庭的接受度。
  • 供体死亡与信息披露：一项研究指出，即使供体已经死亡，了解其死因等医疗信息仍可能对受赠家庭有重要意义，帮助他们决定是否告知受赠者或阻止剩余样本的使用 68。这进一步说明了即使在极端情况下，信息披露的考量依然存在。

3. 国际实践差异：

不同国家和地区在供体-受赠者信息披露方面采取了不同的策略，反映了其对隐私权、知情权和社会价值观的不同权衡。

  • 匿名捐赠为主的国家/地区：在许多国家，长期以来允许匿名捐赠，供体的身份信息不对受赠家庭公开。例如，丹麦在过去就存在匿名捐赠者，但现在一些国家已修改法律，允许捐赠者选择非匿名或身份可识别捐赠。有研究表明，许多匿名捐赠者看重匿名性，不希望与后代建立联系，认为这会“破坏”他们的家庭生活 6163。
  • 身份可识别捐赠或取消匿名的国家/地区：包括英国、瑞典、新西兰、澳大利亚、挪威、奥地利、瑞士和荷兰在内的许多国家已经废除了捐赠者的匿名权，允许或强制要求捐赠者在未来可被身份识别 69。在这些国家，捐赠者同意其身份信息在后代达到一定年龄后可被获取（通常是18岁），旨在保障后代了解自己遗传起源的权利 6470。这种模式在一定程度上缓解了信息不对称的问题，使得在出现重大遗传风险时，沟通渠道更为畅通。
  • 美国实践：在美国，各州法律不一，但整体上对供体匿名性的保护较为严格，尽管也有一些精子库提供“身份披露”的捐赠选项。一些法律案例，如加利福尼亚州的Johnson v. Superior Court一案，就涉及了合同中限制披露精子捐赠者身份的条款是否违反公共政策的问题，法院倾向于认为隐私权并不能完全阻止信息的披露 71。
  • 中国实践：中国的精子库管理相对严格，普遍实行匿名捐赠，且对捐赠者和受赠者的身份信息有严格的保密规定，这使得遗传风险的追溯和披露更为困难。然而，随着社会对知情权和遗传健康关注度的提高，这种模式也面临挑战。

这些国际实践的差异凸显了在确保生殖辅助技术安全、维护各方权益方面的复杂性。在处理癌症遗传风险这类重大问题时，需要更明确的伦理指南、法律框架以及技术支持，以在供体隐私和受赠家庭知情权之间找到一个审慎的平衡点，确保“义务性信息披露”能够以负责任和有效的方式进行。

5.2 全球精子库监管体系的优化建议

面对精子库运作中暴露出的安全隐患和日益凸显的癌症遗传风险问题，优化现有的全球精子库监管体系已刻不容缓。这需要多方协作，从技术、法律、伦理和社会服务等多个层面进行系统性改进，以建立一个更安全、透明和负责任的辅助生殖环境。

1. 建立跨国家/地区的供体遗传信息共享平台：

目前，全球精子库各自为政，信息壁垒严重，这导致同一供体可能在不同国家或地区捐赠，且其遗传信息无法有效整合和共享。一旦某位供体被发现携带致病性遗传变异，现有体系难以迅速追踪并通知所有相关的受赠家庭，从而增加了遗传风险的传播。

  • 平台目标与功能：
    • 统一供体身份识别码：开发全球统一的、加密的供体身份识别系统，确保每一位捐赠者在全球范围内拥有唯一的识别码。这有助于避免供体在不同精子库重复捐赠，并整合其在不同机构的捐赠记录和健康信息。
    • 标准化遗传数据格式：建立国际通用的遗传数据标准和格式，确保不同实验室和精子库生成的基因检测数据可以互操作和共享。这包括统一的变异命名规范、报告格式以及临床意义评估标准。
    • 分级授权访问机制：平台应采用严格的分级授权和加密技术，保障供体隐私。只有在涉及重大公共健康风险（如发现高风险致病性遗传变异可能导致后代严重疾病）且获得伦理委员会批准的情况下，相关医疗机构和遗传咨询师才能有限地访问匿名化的关键遗传信息。
    • 实时信息更新与预警：平台应具备供体健康信息动态更新机制。一旦供体被诊断出新的遗传性疾病或发现携带高风险基因突变，相关信息应及时录入平台，并触发对受赠家庭的匿名预警机制。
  • 实施挑战与对策：实施此类平台面临巨大的法律、伦理和技术挑战，包括数据主权、隐私保护、跨国法律协调以及系统兼容性等。需要联合国、世界卫生组织（WHO）等国际组织牵头，制定全球性的指导原则和框架协议，并鼓励各国政府将其纳入本国法律法规。

2. 强制纳入癌症相关基因检测标准：

当前精子库的基因检测标准差异大，对癌症相关遗传风险的筛查普遍不足。为了有效降低癌症遗传风险，应强制性地将全面癌症相关基因检测纳入供体筛选的标准流程。

  • 扩大基因检测面板：现有筛查主要关注囊性纤维化、脊髓性肌肉萎缩症等少数几种疾病。应将其扩展至包含高外显率的癌症易感基因（如BRCA1/2、TP53、MLH1/MSH2、APC等）以及与常见癌症相关的中等风险基因。随着成本降低和技术进步，全外显子组测序（WES）或特定癌症基因面板检测应成为标准配置。有研究对精子捐赠者进行扩展性携带者筛查（ECS）发现，17.6%的捐赠者因ECS结果而被拒绝，其中甲型地中海贫血、脊髓性肌肉萎缩症和囊性纤维化是最常见的导致拒绝的原因 12。
  • 多基因风险评分（PRS）的应用：研究表明，结合多个常见遗传变异形成的多基因风险评分（PRS）能够更好地预测复杂疾病（如癌症）的风险。应探索将PRS纳入供体筛查的可行性，以更全面地评估供体的整体癌症遗传风险。
  • 定期更新检测标准：随着基因组学研究的深入，新的癌症相关基因和变异不断被发现。监管机构应建立定期审查和更新基因检测标准的机制，确保筛查技术始终处于前沿。
  • 强制性要求与质量控制：各国应通过立法或行业规范，强制要求所有精子库执行统一的、更高标准的癌症相关基因检测。同时，对执行基因检测的实验室进行严格的资质认证和质量控制，确保检测结果的准确性和可靠性。

3. 完善受赠家庭遗传咨询服务：

即使供体经过严格筛选，遗传风险也无法完全消除。因此，为受赠家庭提供专业、持续的遗传咨询服务至关重要。

  • 强制性咨询环节：在选择精子样本前，受赠家庭应强制接受由专业遗传咨询师提供的咨询服务。咨询内容应包括：
    • 遗传风险的全面解读：详细解释供体已进行的基因检测结果，以及可能存在的残余遗传风险，特别是复杂遗传模式和晚发性疾病的风险。
    • 受赠家庭自身遗传风险评估：对受赠方（尤其是女性受方）进行遗传风险评估，以识别与供体遗传信息可能产生的潜在风险组合（如双方都携带同一隐性致病基因的情况）。
    • 知情同意与预期管理：确保受赠家庭充分理解辅助生殖技术的局限性，明确即使有最严格的筛查，仍存在无法预测的遗传风险，并签署知情同意书。
  • 长期追踪与后续咨询：精子库应建立完善的后代健康信息追踪系统，并提供持续的遗传咨询支持。一旦后代出现健康问题，特别是被诊断出遗传性疾病或癌症，应及时启动遗传咨询流程，帮助家庭理解病情，评估遗传原因，并提供治疗建议。此外，应明确供体在捐赠后健康状况发生变化时，精子库如何将匿名化信息传递给受赠家庭的流程。
  • 心理支持与教育：遗传咨询服务还应包含心理支持，帮助受赠家庭应对潜在的遗传风险、疾病诊断带来的心理压力和伦理困境。同时，通过科普教育，提升公众对遗传性疾病和辅助生殖技术的科学认知。
  • 远程医疗的应用：考虑到遗传咨询师资源有限，应积极推广通过远程医疗（如视频咨询）提供遗传咨询服务，以提高服务的可及性和效率 72。

通过上述多维度、系统性的优化建议，全球精子库监管体系有望在保障供体隐私的同时，最大限度地降低遗传风险，为受赠家庭提供更安全、更透明、更具人文关怀的辅助生殖服务。这不仅是对个体家庭健康的负责，也是对整个人类遗传健康的负责。

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参考文献

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Sally R Greenwald, Deborah Cohan, Shannon Weber, et al.
Obstet Gynecol. 2016 Jun;127(6):1097-1099. doi: 10.1097/AOG.0000000000001432.
Currently, both the U.S. Food and Drug Administration and American Society for Reproductive Medicine exclude sperm donation from men who have sex with men. The recommended screening includes questioning donors about their sexual practices and performing a physical examination to look for signs of anal intercourse in addition to standard human immunodeficiency virus (HIV) laboratory testing. The rationale cited is concern over increased risk of HIV transmission in this higher prevalence population. We were unable to find evidence that excluding men who have sex with men or those with signs of anal intercourse on physical examination decreases the false-negative rate of laboratory testing. Current policy allows for men who have sex with men to be prohibited from donating sperm for the use of gestational carriers and therefore discriminates against this population for whom assisted reproductive technology may be their only means of genetic reproduction. We suggest policy revision to include the most advanced HIV laboratory tests and eliminating exclusionary demographics as part of screening.

2Cryopreservation of Sperm: A Review.PubMed

Gururaj M Borate, Ajay Meshram
Cureus. 2022 Nov 12;14(11):e31402. doi: 10.7759/cureus.31402. eCollection 2022 Nov.
Sperm cryopreservation has been used as a sperm preservation solution for infertility issues faced by men undergoing cancer treatment for over 40 years. Recent developments in sperm cryopreservation and its wide variety of therapeutic uses are discussed in this article, which offers a succinct and up-to-date overview of the relevant literature. Recently, sperm cryopreservation has been employed for a wider variety of therapeutic purposes. As a result, sperm freezing is becoming available to a wider variety of patients, which requires more specialized personnel and increases overhead expenses. While sperm cryopreservation before cancer treatment is accessible in many countries, oncology doctors' referral rates and patient participation with cryopreservation services have been observed to be poor. In addition, there are still moral concerns with sperm banking, including whether or not donors' identities should be protected and whether or not a deceased person's sperm should be used after his or her death. This article discusses the recent developments in sperm cryopreservation technology and the moral questions that have arisen around this practice, with an eye toward how a deeper knowledge of these concerns can help more people get access to treatments that might help preserve their fertility. A sperm bank will notify clients about the screenings it does and the background information it gathers on individual donors to guarantee the safety and quality of the sperm they get. The viability and quantity of viable sperm in a thawed sample are often guaranteed by a sperm bank. They will look for very fertile males who can donate sperm that can withstand the freezing and thawing procedure. In many cases, sperm banks advertise their samples as having a certain number of viable sperm per milliliter, and they may provide many sample types for various applications (intracytoplasmic sperm injection and intrauterine insemination).

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D Mortimer
Reprod Biomed Online. 2004 Aug;9(2):134-51. doi: 10.1016/s1472-6483(10)62123-2.
This article focuses on a range of issues that are of current concern to those working in human sperm cryobanking and considers them within a general framework of risk analysis and management, taking into account the available evidence and perceptions of 'best practice' from both the medical and legal perspectives. In particular, issues arising from concerns over the risk of cross-contamination between samples during storage immersed in liquid nitrogen have been analysed in detail. Even though such an occurrence has never been reported for spermatozoa or embryos, and the risk is generally accepted to be vanishingly small, it does represent a finite risk and all reasonable measures should be taken to reduce the chance of its occurring. It is concluded that all methods used to collect, cryopreserve, store, thaw and use cryobanked human spermatozoa must address the risk of contamination from any source throughout the entire process. To assist workers in this area, a series of recommendations as to current best practice are made, based upon conclusions from risk analyses using currently available information.

4Sperm cryopreservation: A review on current molecular cryobiology and advanced approaches.PubMed

Maryam Hezavehei, Mohsen Sharafi, Homa Mohseni Kouchesfahani, et al.
Reprod Biomed Online. 2018 Sep;37(3):327-339. doi: 10.1016/j.rbmo.2018.05.012. Epub 2018 Aug 22.
The cryopreservation of spermatozoa was introduced in the 1960s as a route to fertility preservation. Despite the extensive progress that has been made in this field, the biological and biochemical mechanisms involved in cryopreservation have not been thoroughly elucidated to date. Various factors during the freezing process, including sudden temperature changes, ice formation and osmotic stress, have been proposed as reasons for poor sperm quality post-thaw. Little is known regarding the new aspects of sperm cryobiology, such as epigenetic and proteomic modulation of sperm and trans-generational effects of sperm freezing. This article reviews recent reports on molecular and cellular modifications of spermatozoa during cryopreservation in order to collate the existing understanding in this field. The aim is to discuss current freezing techniques and novel strategies that have been developed for sperm protection against cryo-damage, as well as evaluating the probable effects of sperm freezing on offspring health.

5Advances in sperm cryopreservation in farm animals: Cattle, horse, pig and sheep.PubMed

Iván Yánez-Ortiz, Jaime Catalán, Joan E Rodríguez-Gil, et al.
Anim Reprod Sci. 2022 Nov;246:106904. doi: 10.1016/j.anireprosci.2021.106904. Epub 2021 Dec 3.
Sperm cryopreservation is one of the most important procedures in the development of biotechnologies for assisted reproduction. In some farm animals, the use of cryopreserved sperm has so many benefits for which relevance has become more evident in recent decades. Values for post-thaw sperm quality, however, are variable among species and within individuals of the same species. There is no standardized methodology for each of the stages of the cryopreservation procedure (andrological examination, semen collection, dilution, centrifugation, resuspension of the pellet with the freezing medium, packaging, freezing and post-thaw sperm evaluation), which also contributes to differences among studies. Cryotolerance markers of sperm and seminal plasma (SP) have been evaluated for prediction of ejaculate freezability. In addition, in previous research, there has been a focus on supplementing cryopreservation media with different substances, such as enzymatic and non-enzymatic antioxidants. In most studies, inclusion of these substances have led to improved post-thaw sperm quality and fertilizing capacity as a result of minimizing the adverse effects on sperm structure and function. Another approach is the use of different cryoprotectants. The aim with this review article is to provide an update on sperm cryopreservation in farm animals. The main detrimental effects of cryopreservation are described, including the negative repercussion on reproductive performance. Furthermore, the potential use of molecular biomarkers to predict sperm cryotolerance is discussed, as well as the addition of substances that can mitigate the harmful impact of freezing and thawing on sperm.

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Chuan Huang, Yu-Lin Tang, Jian-Ling Hu, et al.
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In the 1960s, sperm cryopreservation was developed as a method to preserve fertility. Currently, techniques for the cryopreservation of human spermatozoa have been widely used in assisted reproduction. However, although sperm cryobiology has made notable achievements, the optimal method for the recovery of viable spermatozoa after cryopreservation remains elusive. Postthawing sperm quality can be affected by cryoprotectants, ice formation, storage conditions, and osmotic stress during the freezing process. This review discusses recent advances in different cryopreservation techniques, cryoprotectants, and freezing and thawing methods during cryopreservation and new indications for the use of cryopreserved spermatozoa.

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M Nijs, W Ombelet
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Freezing of human sperm is considered a routine procedure in assisted reproductive technology (ART) laboratories. This article considers various aspects of cryopreservation of human sperm. Human sperm show a specific cryophysical behaviour and different sperm freezing protocols have been developed to avoid damage to the sperm cells. The damage can range from impaired motility and reduced viability to damage to the cellular organelles and effects at the molecular level, resulting in an impaired fertilizing potential. As testicular sperm are immature and only a small number can be retrieved, special techniques are required for successful freezing and thawing of these samples. Banking of human sperm has to be performed in a safe and controlled way and different guidelines are necessary to ensure that this is achieved.

8Genetic testing of sperm donors at a human sperm bank in China.PubMed

Chuan Huang, Hui-Lan Wu, Wen-Jun Zhou, et al.
Front Endocrinol (Lausanne). 2022 Sep 20;13:942447. doi: 10.3389/fendo.2022.942447. eCollection 2022.
BACKGROUND: In China, numerous human sperm banks only perform three-generation family history evaluation to exclude genetic diseases with clinical symptoms; therefore, many inherited risks cannot be detected before donor qualification even when a thorough genetic family history evaluation has been performed. Hence, the risk of recessive disease inheritance persists with the current eligibility guidelines in China regarding the donor selection process. METHODS: Retrospective study that reviewed the genetic test analyses and clinical outcomes of young adult men who were qualified sperm donors at the Hunan Province Human Sperm Bank of China from January 1, 2018, to May 1, 2021. We included a total of 3231 qualified sperm donors: all donors underwent primary screening for thalassemia and glucose-6-phosphate dehydrogenase (G6PD) deficiency. Whereafter, 278 of donors underwent genetic testing for specific genes, and 43 donors underwent whole exome sequencing. RESULTS: 2.4% of 3231 qualified sperm donors might have thalassemia and 1.4% might have G6PD deficiency. Sperm donors with thalassemia and G6PD deficiency would be eliminated. Specific gene testing identified 7 of the 278 donors (2.5%) as carriers of at least one pathogenic or likely pathogenic variant in a gene, including 1.9% of 154 donors (3/154) as carrier variants in α-Like or β-Like globin genes, 17.6% of 17 donors (3/17) as carrier variants in , 12.5% of 8 donors (1/8) as carrier variants in . In addition, among the 43 sperm donors carrying the 111 pathogenic/likely pathogenic variants, eight (18.6%) were carriers of pathogenic variants of the gene. The frequency, therefore, was approximately 1 in 5. CONCLUSIONS: The data suggest that used blood routine and RDT can make a preliminary screening of sperm donors, and special gene testing should be performed for sperm donors according to the regional incidence of specific genetic diseases. Meanwhile, whole exome sequencing can be used as a supplementary application in sperm donor genetic testing, and aid a successful and healthy pregnancy. However, industry guidelines must be modified to incorporate its use.

9Current practices of commercial cryobanks in screening prospective donors for genetic disease and reproductive risk.PubMed

E A Conrad, B Fine, B R Hecht, et al.
Int J Fertil Menopausal Stud. 1996 May-Jun;41(3):298-303.
OBJECTIVE: To determine how the screening practices of commercial semen banks vary from published guidelines, which factors influence cryobanks to exclude prospective semen donors for genetic reasons, and the current role of clinical geneticists/genetic counselors in evaluating prospective semen donors. DESIGN: The genetic screening of prospective donors by commercial semen banks was evaluated using written questionnaires completed by bank directors. Responses were analyzed to determine exclusion criteria, adherence to published guidelines, and contribution of genetic professionals. SETTING AND PARTICIPANTS: Semen banks were selected on the basis of membership in the American Association of Tissue Banks and commercial use of semen for artificial insemination by donor. MAIN OUTCOME MEASURE: Semen bank practices as reported by commercial semen bank directors. RESULTS: Of 37 eligible banks, 16 responded. All screen prospective donors by medical/family history and physical examination, 94% have upper age limits; 63% examine for minor physical defects; 56% routinely karyotype; 81% screen men of ethnic groups at risk for Tay Sachs disease, sickle cell disease and thalassemia; 19% screen all donors; 25% screen all donors for cystic fibrosis and 50% only screen if family history positive. Donor rejection was based on three criteria: mode of inheritance of familial disorder, severity of disease, and availability of carrier/confirmatory testing of donor genotype. Ten of 16 banks have no genetic professional on staff. CONCLUSION: Commercial semen banks primarily rely on family history as the major exclusion criterion in genetic screening of donors. Considerable differences exist among semen bank practices in accordance with guidelines published by national agencies. Genetic professionals have a minimal effect overall on evaluation of semen donors.

10Management of the risks for inherited disease in donor-conceived offspring.PubMed

Lauren Isley, Rena E Falk, Jaime Shamonki, et al.
Fertil Steril. 2016 Nov;106(6):1479-1484. doi: 10.1016/j.fertnstert.2016.08.008. Epub 2016 Aug 24.
OBJECTIVE: To illustrate the burden of inherited disease on donor-conceived offspring based on mode of inheritance and to provide guidance on methods of risk reduction. DESIGN: An 8.5-year retrospective review of outcome reports and donor management to summarize medical risks to donor-conceived offspring that presented after the sperm donors were qualified for participation in the donor program. SETTING: Not applicable. PATIENT(S): None. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Description of our experience with newly identified medical risks in donor-conceived offspring as well as how this information was ascertained and managed. RESULT(S): More than half of the indications to restrict donor specimen distribution were due to multifactorial disorders. Approximately one third of the restrictions involved autosomal recessive disorders. The remainder of the restrictions were due to the other indications, including autosomal dominant disorders. CONCLUSION(S): The risks for multifactorial disorders or undiagnosed autosomal dominant disease cannot be significantly reduced or eliminated with routine donor screening procedures. Ongoing risk assessment is essential to identify new genetic risks for autosomal dominant and multifactorial disorders. These assessments require an investment of resources and genetics professionals in the long-term management of changing health information as well as collaboration among gamete facilities, recipients, donors, and their health care providers.

11Genetic testing of sperm donors in China: a survey of current practices.PubMed

Chuan Huang, Qi-Lin Wang, Hui-Lan Wu, et al.
Front Endocrinol (Lausanne). 2023 Jul 14;14:1230621. doi: 10.3389/fendo.2023.1230621. eCollection 2023.
BACKGROUND: The National Health and Family Planning Commission of China (NHFPCC) issued the "Measures for the Management of Human Sperm Banks," which was revised in 2003 and is still in effect today. One of the standard guidelines is that potential donors undergo laboratory testing to exclude infectious and genetic diseases and karyotype analysis. However, patient demands for donor genetic testing have also increased, and only karyotype analysis to exclude genetic diseases is not sufficient to meet these demands. OBJECTIVE: To examine donor genetic screening practices at sperm banks in China and to evaluate the qualifications and skills of genetic counselors at the banks. MATERIALS AND METHODS: An electronic survey was distributed to twenty-seven sperm banks to examine donor genetic screening practices at sperm banks in China and to evaluate the qualifications and skills of genetic counselors at the banks. Twenty-six human sperm banks responded to a 32-question survey about their current practices related to genetic testing of sperm donors. RESULTS: The 26 sperm banks reported that all qualified sperm donors undergo karyotype analysis; 22 banks (84.6%) collected three generations of family history from each qualified sperm donor; 10 (38.5%) reported that they attempted to accommodate special requests from donor semen recipients for particular genetic tests. Only 2 of the 26 (7.7%) sperm banks reported that they performed whole-exome sequencing. At all the sperm banks, consent for genetic testing was obtained as part of the overall contract for sperm donors. Nineteen (73.1%) sperm banks had genetic counselors on their staff, while six (23.1%) had no genetic counselors on their staff but had access to genetic counselors at the hospital. Only one (3.8%) sperm bank had no genetic counselors on their staff or at the hospital. CONCLUSIONS: The need for larger scale genetic testing of donors and recipients and an extensive panel of genetic tests specific to the Chinese population. Additionally, professionally trained geneticists must be employed as genetic counsellors so that the results of genetic tests and their implications can be explained to donors.

12The use of expanded carrier screening of gamete donors.PubMed

Molly R Payne, Anne-Bine Skytte, Joyce C Harper
Hum Reprod. 2021 May 17;36(6):1702-1710. doi: 10.1093/humrep/deab067.
STUDY QUESTION: What are the sperm and egg donor rejection rates after expanded carrier screening (ECS)? SUMMARY ANSWER: Using an ECS panel looking at 46/47 genes, 17.6% of donors were rejected. WHAT IS KNOWN ALREADY: The use of ECS is becoming commonplace in assisted reproductive technology, including testing of egg and sperm donors. Most national guidelines recommend rejection of donors if they are carriers of a genetic disease. If the use of ECS increases, there will be a decline in the number of donors available. STUDY DESIGN, SIZE, DURATION: A review of the current preconception ECS panels available to donors was carried out through an online search. The genetic testing results of donors from Cryos International were analysed to determine how many were rejected on the basis of the ECS. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data on gamete donors and their carrier status was provided by Cryos International, who screen donors using their own bespoke ECS panel. The ECS panels identified through the review were compared to the Cryos International panel and data. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 16 companies and 42 associated ECS panels were reviewed. There were a total of 2673 unique disorders covered by the panels examined, with a mean of 329 disorders screened. None of these disorders were common to all panels. Cryos International screen 46 disorders in males and 47 in females. From 883 candidate donors, 17.6% (155/883) were rejected based on their ECS result. Carriers of alpha-thalassaemia represented the largest proportion of those rejected (19.4%, 30/155), then spinal muscular atrophy (15.5%, 24/155) and cystic fibrosis (14.8%, 23/155). LIMITATIONS, REASONS FOR CAUTION: Panel information was found on company websites and may not have been accurate. WIDER IMPLICATIONS OF THE FINDINGS: This study highlights the need for consistent EU regulations and guidelines that allow genetic matching of gamete donors to their recipients, preventing the need to reject donors who are known carriers. A larger ECS panel would be most beneficial; however, this would not be viable without matching of donors and recipients. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was obtained. J.C.H. is the founder of Global Women Connected, a platform to discuss women's health issues and the Embryology and PGD Academy, who deliver education in clinical embryology. She has been paid to give a lecture by Cryos in 2019. A-B.S. is an employee of Cryos International. TRIAL REGISTRATION NUMBER: N/A.

13Carrier Screening is a Deficient Strategy for Determining Sperm Donor Eligibility and Reducing Risk of Disease in Recipient Children.PubMed

Ari J Silver, Jessica L Larson, Maxwell J Silver, et al.
Genet Test Mol Biomarkers. 2016 Jun;20(6):276-84. doi: 10.1089/gtmb.2016.0014. Epub 2016 Apr 22.
AIMS: DNA-based carrier screening is a standard component of donor eligibility protocols practiced by U.S. sperm banks. Applicants who test positive for carrying a recessive disease mutation are typically disqualified. The aim of our study was to examine the utility of a range of screening panels adopted by the industry and the effectiveness of the screening paradigm in reducing a future child's risk of inheriting disease. METHODS: A cohort of 27 donor applicants, who tested negative on an initial cystic fibrosis carrier test, was further screened with three expanded commercial carrier testing panels. These results were then compared to a systematic analysis of the applicants' DNA using next-generation sequencing (NGS) data. RESULTS: The carrier panels detected serious pediatric disease mutations in one, four, or six donor applicants. Because each panel screens distinct regions of the genome, no single donor was uniformly identified as carrier positive by all three panels. In contrast, systematic NGS analysis identified all donors as carriers of one or more mutations associated with severe monogenic pediatric disease. These included 30 variants classified as "pathogenic" based on clinical observation and 66 with a high likelihood of causing gene dysfunction. CONCLUSION: Despite tremendous advances in variant identification, understanding, and analysis, the vast majority of disease-causing mutation combinations remain undetected by commercial carrier screening panels, which cover a narrow, and often distinct, subset of genes and mutations. The biological reality is that all donors and recipients carry serious recessive disease mutations. This challenges the utility of any screening protocol that anchors donor eligibility to carrier status. A more effective approach to reducing recessive disease risk would consider joint comprehensive analysis of both donor and recipient disease mutations. This type of high-resolution recessive disease risk analysis is now available and affordable, but industry practice must be modified to incorporate its use.

14Application of clinical exome sequencing in sperm donor screening in China.PubMed

Jie Huang, Man Yu, Jie Yang, et al.
J Assist Reprod Genet. 2025 Jul;42(7):2273-2283. doi: 10.1007/s10815-025-03540-3. Epub 2025 Jun 11.
PURPOSE: In China, genetic testing is conducted by only a small proportion of sperm banks. Traditional sperm donor screening primarily relies on family history to exclude individuals with known genetic diseases. However, this method does not fully address the genetic risks associated with recessive and late-onset dominant disorders. This study aims to conduct genetic testing for sperm donors using high-coverage clinical exome sequencing (CES) to identify disease-causing mutations in voluntarily submitted blood samples. METHODS: Peripheral blood samples from sperm donors were collected for clinical exome sequencing (CES), which targeted the coding exons of approximately 5595 clinically relevant disease-causing genes. RESULTS: Among the 391 donors, 372 (95.14%) were identified as carriers of at least one pathogenic or likely pathogenic variant, including those related to autosomal recessive, digenic recessive, and complex inheritance patterns. The carrier rate for autosomal dominant and X-linked conditions was 4.86% (19/391). On average, each donor carried 3.53 recessive genetic defects. The most frequent variants were found in UGT1 A, FLG, and GJB2. Six donors with high-frequency SMN1 exon 7-8 deletions were excluded. Ultimately, 45 donors (11.51%) were rejected, resulting in a qualification rate of 88.49%. CONCLUSIONS: Clinical exome sequencing (CES) of sperm donors identified carriers of genetic conditions and excluded those with a history of dominant genetic disorders. Additionally, joint donor-recipient matching for recessive gene carriers can reduce the risk of congenital defects in offspring conceived through assisted reproduction, ensuring genetic compatibility and preventing unintended transmission of genetic disorders.

15FDA approved? A critique of the artificial insemination industry in the United States.PubMed

K M Ginsberg
Univ Mich J Law Reform. 1997 Summer;30(4):823-51.
Artificial insemination by donor is becoming an increasingly popular means to achieving parenthood. While the majority of couples use artificial insemination to overcome fertility problems, many recipients use artificial insemination to avoid passing a genetic disease to their children. However, case studies reveal the inherent dangers of artificial insemination, namely the lack of proper screening methods to avoid passing genetic diseases to children born by artificial insemination. State-by-state regulation, federal guidelines, and private adjudication have all proven to be inadequate methods of regulating the artificial insemination industry. Ginsberg proposes federal regulation as the only means of achieving a safe artificial insemination industry. The proposed federal regulation would include better genetic screening, a more efficient national sperm donor system, and limited disclosure to recipients of artificial insemination and their children. These measures would help to ensure that couples using artificial insemination get what they expect--healthy sperm, a safe artificial insemination process, and ultimately, a healthy child.

16Sperm is subject to product liability laws in the US.PubMed

Norra MacReady
Lancet Oncol. 2009 May;10(5):451. doi: 10.1016/s1470-2045(09)70132-9.

17"Obligated aliens": recognizing sperm donors' ethical obligation to disclose genetic information.PubMed

Sivan Tamir
Kennedy Inst Ethics J. 2013 Mar;23(1):19-52. doi: 10.1353/ken.2013.0001.
Sperm donors' obligations are typically constrained to the immediate circumstances surrounding the donation and to its time frame. This paper makes the case for recognizing an ongoing ethical obligation that binds sperm donors to disclose, in a timely manner, meaningful genetic information to recipients and donor-conceived children. The paper delineates and conceptualizes the suggested (potentially reciprocal) duty and argues that it is not the genetic link between the donor and the donor-conceived child that binds donors by said duty, but rather social responsibility. Accordingly, an original perception of the donor as an obligated alien is suggested and developed. The main thesis of the paper is supported inter alia by a comparison between transmitting infectious diseases and passing faulty genes on to donor-conceived children. The paper also provides an in-depth analysis of the conflicting interests of the parties generated by such an obligation and proposes a model for embedding this ethical duty in a (legal) contractual framework.

18Environmental, occupational and familial risks for testicular cancer: a hospital-based case-control study.PubMed

Marie Walschaerts, Audrey Muller, Jacques Auger, et al.
Int J Androl. 2007 Aug;30(4):222-9. doi: 10.1111/j.1365-2605.2007.00805.x.
Testicular cancer (TC) risk factors remain largely unknown, except for personal history of cryptorchidism and familial history of TC. We conducted a hospital-based case-control study on familial, environmental and occupational conditions in which we compared 229 cases and 800 controls. TC was correlated with cryptorchidism (OR = 3.02; CI: 1.90-4.79), a history of cryptorchidism in relatives (OR = 2.85; CI: 1.70-4.79), and TC (OR = 9.58; CI: 4.01-22.88], prostate cancer (OR = 1.80; CI: 1.08-3.02) and breast cancer (OR = 1.77; CI: 1.20-2.60) in relatives. Living in a rural area or having regular gardening activity (growing fruit or vegetables) was associated with an increased risk of TC (OR = 1.63; CI: 1.16-2.29; OR = 1.84; CI: 1.23-2.75). Regarding occupation, we found a relationship with employment in metal trimming (OR = 1.96; CI: 1.00-3.86), chemical manufacture (OR = 1.88; CI: 1.14-3.10), industrial production of glue (OR = 2.21; CI: 1.15-4.25), and welding (OR = 2.84; CI: 1.51-5.35). In a multivariate model, only a history of cryptorchidism in the men, cryptorchidism in relatives, TC, and breast cancer remained significant. Our findings contribute further evidence to a pattern of TC risk factors, which include the significant weight of personal reproductive history and also of testicular and breast cancer in relatives. By including in a multivariate model variables linked to environmental and occupational exposure and related to familial cancer history, neither living in a rural area nor any occupational exposure appeared to be a potential environmental TC risk factor.

19Genetic testing of sperm donors: survey of current practices.PubMed

Charles A Sims, Pamela Callum, Marilyn Ray, et al.
Fertil Steril. 2010 Jun;94(1):126-9. doi: 10.1016/j.fertnstert.2009.01.139. Epub 2009 Apr 1.
OBJECTIVE: To determine which genetic tests are being performed on sperm donor applicants in the United States. DESIGN: An electronic survey was distributed to 26 sperm banks to evaluate their genetic testing practices. SETTING: Sperm banks in the United States. PATIENT(S): Not applicable. INTERVENTION(S): None. Survey of current practices. MAIN OUTCOME MEASURE(S): Survey of current practices. RESULT(S): Cystic fibrosis (CF) carrier screening, chromosome analyses, and hemoglobin evaluations are performed on the majority of sperm donor applicants. Tay-Sachs disease carrier screening is performed on most donors with Jewish heritage but there is significant variation in screening for other disorders that occur with increased frequency in this population. Individual sperm banks use different laboratory tests for evaluation of the same conditions, with each test having different carrier detection rates and interpretations. CONCLUSION(S): The genetic testing performed on sperm donors varies significantly at sperm banks across the United States. Therefore, recipients should be clearly informed about the specific evaluations performed on their donor of interest. Thus it is important that sperm banks employ genetic professionals to evaluate the donors' and recipients' medical histories and perform a genetic risk assessment. This will allow clients to make informed decisions about use of semen specimens from an anonymous sperm donor.

20Multidisciplinary management for Peutz-Jeghers syndrome and prevention of vertical transmission to offspring using preimplantation genetic testing.PubMed

Xiqiao Xu, Ruifeng Song, Kaiyue Hu, et al.
Orphanet J Rare Dis. 2022 Feb 21;17(1):64. doi: 10.1186/s13023-022-02221-z.
BACKGROUND: Peutz Jeghers syndrome (PJS) is an autosomal dominant genetic disorder caused by STK11 mutation with a predisposition to gastrointestinal polyposis and cancer. PJS patients suffer poor quality of life and are highly concerned about whether deleterious mutations transmit to their offspring. Therefore, this study aimed to propose feasible clinical management and provide effective preimplantation genetic testing for monogenic defect (PGT-M) strategies to protect offspring from inheriting the disease. METHODS: A hospital-based clinical retrospective analysis reviewing the clinical characteristics and fertility aspects was first conducted on 51 PJS patients at the First Affiliated Hospital of Zhengzhou University between January 2016 and March 2021. Among the 51 patients, the PGT-M strategy was further carried out in 4 couples, which started with a biopsy of the trophectoderm cells of embryos and whole genome amplification using multiple displacement amplification. Thereafter, single nucleotide polymorphism linkage analyses based on karyomapping were performed with copy number variations of the embryos identified simultaneously. Finally, prenatal diagnosis was used to verify the validity of the PGT-M results. RESULTS: A comprehensive management flowchart adopted by the multidisciplinary team model was formulated mainly focusing on clinical genetic and gastrointestinal aspects. Under the guidelines of this management, 32 embryos from 4 PJS pedigrees were diagnosed and 2 couples successfully conceived healthy babies free of the STK11 pathogenic mutation. CONCLUSIONS: Our comprehensive management could help affected families avoid having children with PJS through preimplantation genetic testing and provide meaningful guidance for multidisciplinary clinical practice on PJS.

21Distribution and transmission of copy number variations of uncertain significance in 105 trios.PubMed

Qiang Wen, Xiu Wang, Hao Zhang, et al.
Mol Genet Genomic Med. 2022 Sep;10(9):e2030. doi: 10.1002/mgg3.2030. Epub 2022 Aug 9.
BACKGROUND: The distribution and genetic characteristics of copy number variations (CNVs) remain unclear. Here, we investigated the distribution and transmission of CNVs of uncertain significance in fetuses. METHODS: Low-coverage massively parallels CNV sequencing of 105 families (parents and their fetuses) was performed to identify fetal CNVs of uncertain significance. RESULTS: In the 105 fetuses, 176 CNVs of uncertain significance were detected, and the average number of CNVs carried by fetuses was 1.68 ± 0.80. Among the CNVs carried by the fetuses, 79.8% were inherited (~90.0% of the fetuses) and 20.2% were new mutations (~30.0% of the fetuses). We found that 58.9% CNVs were of maternal origin and 41.1% were of paternal origin. Among the CNV subtypes, de novo CNV distribution was significantly different from inherited CNV distribution. There was no difference in the distribution of maternal and paternal CNV subtypes in the fetuses. The proportion of microdeletions (36.7%) and microduplications (63.3%) was similar in the fetuses and parents. Furthermore, we found that when parents carried more CNVs of uncertain significance, the chance of passing them on to their offspring decreased. CONCLUSION: This study deepens our understanding of the genetic mechanisms associated with CNV transmission to assist clinicians in prenatal counseling.

22Transmission distortion and genetic incompatibilities between alleles in a multigenerational mouse advanced intercross line.PubMed

Danny Arends, Stefan Kärst, Sebastian Heise, et al.
Genetics. 2022 Jan 4;220(1). doi: 10.1093/genetics/iyab192.
While direct additive and dominance effects on complex traits have been mapped repeatedly, additional genetic factors contributing to the heterogeneity of complex traits have been scarcely investigated. To assess genetic background effects, we investigated transmission ratio distortions (TRDs) of alleles from parent to offspring using an advanced intercross line (AIL) of an initial cross between the mouse inbred strains C57BL/6NCrl (B6N) and BFMI860-12 [Berlin Fat Mouse Inbred (BFMI)]. A total of 341 males of generation 28 and their respective 61 parents and 66 grandparents were genotyped using Mega Mouse Universal Genotyping Arrays. TRDs were investigated using allele transmission asymmetry tests, and pathway overrepresentation analysis was performed. Sequencing data were used to test for overrepresentation of nonsynonymous SNPs (nsSNPs) in TRD regions. Genetic incompatibilities were tested using the Bateson-Dobzhansky-Muller two-locus model. A total of 62 TRD regions were detected, many in close proximity to the telocentric centromere. TRD regions contained 44.5% more nsSNPs than randomly selected regions (182 vs 125.9 ± 17.0, P < 1 × 10-4). Testing for genetic incompatibilities between TRD regions identified 29 genome-wide significant incompatibilities between TRD regions [P(BF) < 0.05]. Pathway overrepresentation analysis of genes in TRD regions showed that DNA methylation, epigenetic regulation of RNA, and meiotic/meiosis regulation pathways were affected independent of the parental origin of the TRD. Paternal BFMI TRD regions showed overrepresentation in the small interfering RNA biogenesis and in the metabolism of lipids and lipoproteins. Maternal B6N TRD regions harbored genes involved in meiotic recombination, cell death, and apoptosis pathways. The analysis of genes in TRD regions suggests the potential distortion of protein-protein interactions influencing obesity and diabetic retinopathy as a result of disadvantageous combinations of allelic variants in Aass, Pgx6, and Nme8. Using an AIL significantly improves the resolution at which we can investigate TRD. Our analysis implicates distortion of protein-protein interactions as well as meiotic drive as the underlying mechanisms leading to the observed TRD in our AIL. Furthermore, genes with large amounts of nsSNPs located in TRD regions are more likely to be involved in pathways that are related to the phenotypic differences between the parental strains. Genes in these TRD regions provide new targets for investigating genetic adaptation, protein-protein interactions, and determinants of complex traits such as obesity.

23Genome-wide association studies and Mendelian randomization analyses provide insights into the causes of early-onset colorectal cancer.PubMed

R S Laskar, C Qu, J R Huyghe, et al.
Ann Oncol. 2024 Jun;35(6):523-536. doi: 10.1016/j.annonc.2024.02.008. Epub 2024 Feb 24.
BACKGROUND: The incidence of early-onset colorectal cancer (EOCRC; diagnosed <50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. CRC has strong genetic and environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization (MR) analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC. PATIENTS AND METHODS: We conducted a GWAS meta-analysis of 6176 EOCRC cases and 65 829 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), and the UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample MR. RESULTS: We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, which were not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (odds ratio 1.80, 95% confidence interval 1.47-2.22) but show that most of the common genetic susceptibility was from noncoding signals enriched in epigenetic markers present in gastrointestinal tract cells. We identified new EOCRC-susceptibility genes, and in addition to pathways such as transforming growth factor (TGF) β, suppressor of Mothers Against Decapentaplegic (SMAD), bone morphogenetic protein (BMP) and phosphatidylinositol kinase (PI3K) signaling, our study highlights a role for insulin signaling and immune/infection-related pathways in EOCRC. In our MR analyses, we found novel evidence of probable causal associations for higher levels of body size and metabolic factors-such as body fat percentage, waist circumference, waist-to-hip ratio, basal metabolic rate, and fasting insulin-higher alcohol drinking, and lower education attainment with increased EOCRC risk. CONCLUSIONS: Our novel findings indicate inherited susceptibility to EOCRC and suggest modifiable lifestyle and metabolic targets that could also be used to risk-stratify individuals for personalized screening strategies or other interventions.

24Genome-wide Association Study of Bladder Cancer Reveals New Biological and Translational Insights.PubMed

Stella Koutros, Lambertus A Kiemeney, Parichoy Pal Choudhury, et al.
Eur Urol. 2023 Jul;84(1):127-137. doi: 10.1016/j.eururo.2023.04.020. Epub 2023 May 19.
BACKGROUND: Genomic regions identified by genome-wide association studies (GWAS) for bladder cancer risk provide new insights into etiology. OBJECTIVE: To identify new susceptibility variants for bladder cancer in a meta-analysis of new and existing genome-wide genotype data. DESIGN, SETTING, AND PARTICIPANTS: Data from 32 studies that includes 13,790 bladder cancer cases and 343,502 controls of European ancestry were used for meta-analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: Log-additive associations of genetic variants were assessed using logistic regression models. A fixed-effects model was used for meta-analysis of the results. Stratified analyses were conducted to evaluate effect modification by sex and smoking status. A polygenic risk score (PRS) was generated on the basis of known and novel susceptibility variants and tested for interaction with smoking. RESULTS AND LIMITATIONS: Multiple novel bladder cancer susceptibility loci (6p.22.3, 7q36.3, 8q21.13, 9p21.3, 10q22.1, 19q13.33) as well as improved signals in three known regions (4p16.3, 5p15.33, 11p15.5) were identified, bringing the number of independent markers at genome-wide significance (p < 5 × 10) to 24. The 4p16.3 (FGFR3/TACC3) locus was associated with a stronger risk for women than for men (p-interaction = 0.002). Bladder cancer risk was increased by interactions between smoking status and genetic variants at 8p22 (NAT2; multiplicative p value for interaction [p] = 0.004), 8q21.13 (PAG1; p = 0.01), and 9p21.3 (LOC107987026/MTAP/CDKN2A; p = 0.02). The PRS based on the 24 independent GWAS markers (odds ratio per standard deviation increase 1.49, 95% confidence interval 1.44-1.53), which also showed comparable results in two prospective cohorts (UK Biobank, PLCO trial), revealed an approximately fourfold difference in the lifetime risk of bladder cancer according to the PRS (e.g., 1st vs 10th decile) for both smokers and nonsmokers. CONCLUSIONS: We report novel loci associated with risk of bladder cancer that provide clues to its biological underpinnings. Using 24 independent markers, we constructed a PRS to stratify lifetime risk. The PRS combined with smoking history, and other established risk factors, has the potential to inform future screening efforts for bladder cancer. PATIENT SUMMARY: We identified new genetic markers that provide biological insights into the genetic causes of bladder cancer. These genetic risk factors combined with lifestyle risk factors, such as smoking, may inform future preventive and screening strategies for bladder cancer.

25Identification of novel protein biomarkers and drug targets for colorectal cancer by integrating human plasma proteome with genome.PubMed

Jing Sun, Jianhui Zhao, Fangyuan Jiang, et al.
Genome Med. 2023 Sep 19;15(1):75. doi: 10.1186/s13073-023-01229-9.
BACKGROUND: The proteome is a major source of therapeutic targets. We conducted a proteome-wide Mendelian randomization (MR) study to identify candidate protein markers and therapeutic targets for colorectal cancer (CRC). METHODS: Protein quantitative trait loci (pQTLs) were derived from seven published genome-wide association studies (GWASs) on plasma proteome, and summary-level data were extracted for 4853 circulating protein markers. Genetic associations with CRC were obtained from a large-scale GWAS meta-analysis (16,871 cases and 26,328 controls), the FinnGen cohort (4957 cases and 304,197 controls), and the UK Biobank (9276 cases and 477,069 controls). Colocalization and summary-data-based MR (SMR) analyses were performed sequentially to verify the causal role of candidate proteins. Single cell-type expression analysis, protein-protein interaction (PPI), and druggability evaluation were further conducted to detect the specific cell type with enrichment expression and prioritize potential therapeutic targets. RESULTS: Collectively, genetically predicted levels of 13 proteins were associated with CRC risk. Elevated levels of two proteins (GREM1, CHRDL2) and decreased levels of 11 proteins were associated with an increased risk of CRC, among which four (GREM1, CLSTN3, CSF2RA, CD86) were prioritized with the most convincing evidence. These protein-coding genes are mainly expressed in tissue stem cells, epithelial cells, and monocytes in colon tumor tissue. Two interactive pairs of proteins (GREM1 and CHRDL2; MMP2 and TIMP2) were identified to be involved in osteoclast differentiation and tumorigenesis pathways; four proteins (POLR2F, CSF2RA, CD86, MMP2) have been targeted for drug development on autoimmune diseases and other cancers, with the potentials of being repurposed as therapeutic targets for CRC. CONCLUSIONS: This study identified several protein biomarkers to be associated with CRC risk and provided new insights into the etiology and promising targets for the development of screening biomarkers and therapeutic drugs for CRC.

26Assessment of a Polygenic Risk Score in Screening for Prostate Cancer.PubMed

Jana K McHugh, Elizabeth K Bancroft, Edward Saunders, et al.
N Engl J Med. 2025 Apr 10;392(14):1406-1417. doi: 10.1056/NEJMoa2407934.
BACKGROUND: The incidence of prostate cancer is increasing. Screening with an assay of prostate-specific antigen (PSA) has a high rate for false positive results. Genomewide association studies have identified common germline variants in persons with prostate cancer, which can be used to calculate a polygenic risk score associated with risk of prostate cancer. METHODS: We recruited persons 55 to 69 years of age from primary care centers in the United Kingdom. Using germline DNA extracted from saliva, we derived polygenic risk scores from 130 variants known to be associated with an increased risk of prostate cancer. Participants with a polygenic risk score in the 90th percentile or higher were invited to undergo prostate cancer screening with multiparametric magnetic resonance imaging (MRI) and transperineal biopsy, irrespective of PSA level. RESULTS: Among 40,292 persons invited to participate, 8953 (22.2%) expressed interest in participating and 6393 had their polygenic risk score calculated; 745 (11.7%) had a polygenic risk score in the 90th percentile or higher and were invited to undergo screening. Of these 745 participants, 468 (62.8%) underwent MRI and prostate biopsy; prostate cancer was detected in 187 participants (40.0%). The median age at diagnosis was 64 years (range, 57 to 73). Of the 187 participants with cancer, 103 (55.1%) had prostate cancer classified as intermediate or higher risk according to the 2024 National Comprehensive Cancer Network (NCCN) criteria, so treatment was indicated; cancer would not have been detected in 74 (71.8%) of these participants according to the prostate cancer diagnostic pathway currently used in the United Kingdom (high PSA level and positive MRI results). In addition, 40 of the participants with cancer (21.4%) had disease classified as unfavorable intermediate risk or as high or very high risk according to NCCN criteria. CONCLUSIONS: In a prostate cancer screening program involving participants in the top decile of risk as determined by a polygenic risk score, the percentage found to have clinically significant disease was higher than the percentage that would have been identified with the use of PSA or MRI. (Funded by the European Research Council Seventh Framework Program and others; BARCODE1 ClinicalTrials.gov number, NCT03857477.).

27Plasma proteomic and polygenic profiling improve risk stratification and personalized screening for colorectal cancer.PubMed

Jing Sun, Yue Liu, Jianhui Zhao, et al.
Nat Commun. 2024 Oct 15;15(1):8873. doi: 10.1038/s41467-024-52894-2.
This study aims to identify colorectal cancer (CRC)-related proteomic profiles and develop a prediction model for CRC onset by integrating proteomic profiles with genetic and non-genetic factors (QCancer-15) to improve the risk stratification and estimate of personalized initial screening age. Here, using a two-stage strategy, we prioritize 15 protein biomarkers as predictors to construct a protein risk score (ProS). The risk prediction model integrating proteomic profiles with polygenic risk score (PRS) and QCancer-15 risk score (QCancer-S) shows improved performance (C-statistic: 0.79 vs. 0.71, P = 4.94E-03 in training cohort; 0.75 vs 0.69, P = 5.49E-04 in validation cohort) and net benefit than QCancer-S alone. The combined model markedly stratifies the risk of CRC onset. Participants with high ProS, PRS, or combined risk score are proposed to start screening at age 46, 41, or before 40 years old. In this work, the integration of blood proteomics with PRS and QCancer-15 demonstrates improved performance for risk stratification and clinical implication for the derivation of risk-adapted starting ages of CRC screening, which may contribute to the decision-making process for CRC screening.

28Integrating genome-wide polygenic risk scores and non-genetic risk to predict colorectal cancer diagnosis using UK Biobank data: population based cohort study.PubMed

Sarah E W Briggs, Philip Law, James E East, et al.
BMJ. 2022 Nov 9;379:e071707. doi: 10.1136/bmj-2022-071707.
OBJECTIVE: To evaluate the benefit of combining polygenic risk scores with the QCancer-10 (colorectal cancer) prediction model for non-genetic risk to identify people at highest risk of colorectal cancer. DESIGN: Population based cohort study. SETTING: Data from the UK Biobank study, collected between March 2006 and July 2010. PARTICIPANTS: 434 587 individuals with complete data for genetics and QCancer-10 predictions were included in the QCancer-10 plus polygenic risk score modelling and validation cohorts. MAIN OUTCOME MEASURES: Prediction of colorectal cancer diagnosis by genetic, non-genetic, and combined risk models. Using data from UK Biobank, six different polygenic risk scores for colorectal cancer were developed using LDpred2 polygenic risk score software, clumping, and thresholding approaches, and a model based on genome-wide significant polymorphisms. The top performing genome-wide polygenic risk score and the score containing genome-wide significant polymorphisms were combined with QCancer-10 and performance was compared with QCancer-10 alone. Case-control (logistic regression) and time-to-event (Cox proportional hazards) analyses were used to evaluate risk model performance in men and women. RESULTS: Polygenic risk scores derived using the LDpred2 program performed best, with an odds ratio per standard deviation of 1.584 (95% confidence interval 1.536 to 1.633), and top age and sex adjusted C statistic of 0.733 (95% confidence interval 0.710 to 0.753) in logistic regression models in the validation cohort. Integrated QCancer-10 plus polygenic risk score models out-performed QCancer-10 alone. In men, the integrated LDpred2 model produced a C statistic of 0.730 (0.720 to 0.741) and explained variation of 28.2% (26.3 to 30.1), compared with 0.693 (0.682 to 0.704) and 21.0% (18.9 to 23.1) for QCancer-10 alone. In women, the C statistic for the integrated LDpred2 model was 0.687 (0.673 to 0.702) and explained variation was 21.0% (18.7 to 23.7), compared with 0.645 (0.631 to 0.659) and 12.4% (10.3 to 14.6) for QCancer-10 alone. In the top 20% of individuals at highest absolute risk, the sensitivity and specificity of the integrated LDpred2 models for predicting colorectal cancer diagnosis was 47.8% and 80.3% respectively in men, and 42.7% and 80.1% respectively in women, with increases in absolute risk in the top 5% of risk in men of 3.47-fold and in women of 2.77-fold compared with the median. Illustrative decision curve analysis indicated a small incremental improvement in net benefit with QCancer-10 plus polygenic risk score models compared with QCancer-10 alone. CONCLUSIONS: Integrating polygenic risk scores with QCancer-10 modestly improves risk prediction over use of QCancer-10 alone. Given that QCancer-10 data can be obtained relatively easily from health records, use of polygenic risk score in risk stratified population screening for colorectal cancer currently has no clear justification. The added benefit, cost effectiveness, and acceptability of polygenic risk scores should be carefully evaluated in a real life screening setting before implementation in the general population.

29Risk assessment for colorectal cancer via polygenic risk score and lifestyle exposure: a large-scale association study of East Asian and European populations.PubMed

Junyi Xin, Mulong Du, Dongying Gu, et al.
Genome Med. 2023 Jan 24;15(1):4. doi: 10.1186/s13073-023-01156-9.
BACKGROUND: The genetic architectures of colorectal cancer are distinct across different populations. To date, the majority of polygenic risk scores (PRSs) are derived from European (EUR) populations, which limits their accurate extrapolation to other populations. Here, we aimed to generate a PRS by incorporating East Asian (EAS) and EUR ancestry groups and validate its utility for colorectal cancer risk assessment among different populations. METHODS: A large-scale colorectal cancer genome-wide association study (GWAS), harboring 35,145 cases and 288,934 controls from EAS and EUR populations, was used for the EAS-EUR GWAS meta-analysis and the construction of candidate EAS-EUR PRSs via different approaches. The performance of each PRS was then validated in external GWAS datasets of EAS (727 cases and 1452 controls) and EUR (1289 cases and 1284 controls) ancestries, respectively. The optimal PRS was further tested using the UK Biobank longitudinal cohort of 355,543 individuals and ultimately applied to stratify individual risk attached by healthy lifestyle. RESULTS: In the meta-analysis across EAS and EUR populations, we identified 48 independent variants beyond genome-wide significance (P < 5 × 10) at previously reported loci. Among 26 candidate EAS-EUR PRSs, the PRS-CSx approach-derived PRS (defined as PRS) that harbored genome-wide variants achieved the optimal discriminatory ability in both validation datasets, as well as better performance in the EAS population compared to the PRS derived from known variants. Using the UK Biobank cohort, we further validated a significant dose-response effect of PRS on incident colorectal cancer, in which the risk was 2.11- and 3.88-fold higher in individuals with intermediate and high PRS than in the low score subgroup (P = 8.15 × 10). Notably, the detrimental effect of being at a high genetic risk could be largely attenuated by adherence to a favorable lifestyle, with a 0.53% reduction in 5-year absolute risk. CONCLUSIONS: In summary, we systemically constructed an EAS-EUR PRS to effectively stratify colorectal cancer risk, which highlighted its clinical implication among diverse ancestries. Importantly, these findings also supported that a healthy lifestyle could reduce the genetic impact on incident colorectal cancer.

30Cancer epigenetics: from mechanism to therapy.PubMed

Mark A Dawson, Tony Kouzarides
Cell. 2012 Jul 6;150(1):12-27. doi: 10.1016/j.cell.2012.06.013.
The epigenetic regulation of DNA-templated processes has been intensely studied over the last 15 years. DNA methylation, histone modification, nucleosome remodeling, and RNA-mediated targeting regulate many biological processes that are fundamental to the genesis of cancer. Here, we present the basic principles behind these epigenetic pathways and highlight the evidence suggesting that their misregulation can culminate in cancer. This information, along with the promising clinical and preclinical results seen with epigenetic drugs against chromatin regulators, signifies that it is time to embrace the central role of epigenetics in cancer.

31Cancer Epigenetics: An Overview.PubMed

Félix Recillas-Targa
Arch Med Res. 2022 Dec;53(8):732-740. doi: 10.1016/j.arcmed.2022.11.003. Epub 2022 Nov 18.
Cancer is a complex disease caused by genetic and epigenetic alterations in the control of cell division. Findings from the field of cancer genomics and epigenomics have increased our understanding of the origin and evolution of tumorigenic processes, greatly advancing our knowledge of the molecular etiology of cancer. Consequently, any contemporary view of cancer research must consider tumorigenesis as a cellular phenomenon that is a result of the interplay between genetic and epigenetic mutations and their interaction with environmental factors, including our microbiome, that influences cellular metabolism and proliferation rates. The integration and better knowledge of these processes will help us to improve diagnosis, prognosis, and future genetic and epigenetic therapies. Here, I present an overview of the epigenetic processes that are affected in cancer and how they contribute to the onset and progression of the disease. Finally, I discuss how the development of sophisticated experimental approaches and computational tools, including novel ways to exploit large data sets, could contribute to the better understanding and treatment of cancer.

32Histone Modifications and their Role in Epigenetics of Cancer.PubMed

Sumera Zaib, Nehal Rana, Imtiaz Khan
Curr Med Chem. 2022;29(14):2399-2411. doi: 10.2174/0929867328666211108105214.
Epigenetic regulations play a crucial role in the expression of various genes that are important in the normal cell function. Any alteration in these epigenetic mechanisms can lead to the modification of histone and DNA, resulting in the silencing or enhanced expression of some genes causing various diseases. Acetylation, methylation, ribosylation, or phosphorylation of histone proteins modifies its interaction with the DNA, consequently changing the ratio of heterochromatin and euchromatin. Terminal lysine residues of histone proteins serve as potential targets of such epigenetic modifications. The current review focuses on the histone modifications, and their contributing factors; the role of these modifications on metabolism leads to cancer, and methylation of histone in cancer affects the DNA repair mechanisms.

33Cancer Epigenetics, Tumor Immunity, and Immunotherapy.PubMed

Jian Cao, Qin Yan
Trends Cancer. 2020 Jul;6(7):580-592. doi: 10.1016/j.trecan.2020.02.003. Epub 2020 Mar 31.
Epigenetic mechanisms, including DNA methylation, histone post-translational modifications, and chromatin structure regulation, are critical for the interactions between tumor and immune cells. Emerging evidence shows that tumors commonly hijack various epigenetic mechanisms to escape immune restriction. As a result, the pharmaceutical modulation of epigenetic regulators, including 'writers', 'readers', 'erasers', and 'remodelers', is able to normalize the impaired immunosurveillance and/or trigger antitumor immune responses. Thus, epigenetic targeting agents are attractive immunomodulatory drugs and will have major impacts on immuno-oncology. Here, we discuss epigenetic regulators of the cancer-immunity cycle and current advances in developing epigenetic therapies to boost anticancer immune responses, either alone or in combination with current immunotherapies.

34Epigenetic alterations in cancer.PubMed

Suganya Ilango, Biswaranjan Paital, Priyanka Jayachandran, et al.
Front Biosci (Landmark Ed). 2020 Mar 1;25(6):1058-1109. doi: 10.2741/4847.
Genetic and epigenetic modifications in DNA contribute to altered gene expression in aging and cancer. In human cancers, epigenetic changes such as DNA methylation, histone modifications, micro RNAs and nucleosome remodelling all control gene expression. The link between the genetics and epigenetics in cancer is further shown by existence of aberrant metabolism and biochemical pathways in cancer or mutation in genes that are epigenetic players. Reversal of these epigenetic changes has been clearly shown to have therapeutic value in various forms of lymphoma and preleukemia and similar results are appearing for the treatment of solid tumors. In this review, we discuss the functional effects of epigenetic changes inducible by hypoxia, the epigenetic alterations in cancer and how they contribute to tumor progression and their relevance to epigenetic therapy.

35Identification of genomic alterations in oesophageal squamous cell cancer.PubMed

Yongmei Song, Lin Li, Yunwei Ou, et al.
Nature. 2014 May 1;509(7498):91-5. doi: 10.1038/nature13176. Epub 2014 Mar 16.
Oesophageal cancer is one of the most aggressive cancers and is the sixth leading cause of cancer death worldwide. Approximately 70% of global oesophageal cancer cases occur in China, with oesophageal squamous cell carcinoma (ESCC) being the histopathological form in the vast majority of cases (>90%). Currently, there are limited clinical approaches for the early diagnosis and treatment of ESCC, resulting in a 10% five-year survival rate for patients. However, the full repertoire of genomic events leading to the pathogenesis of ESCC remains unclear. Here we describe a comprehensive genomic analysis of 158 ESCC cases, as part of the International Cancer Genome Consortium research project. We conducted whole-genome sequencing in 17 ESCC cases and whole-exome sequencing in 71 cases, of which 53 cases, plus an additional 70 ESCC cases not used in the whole-genome and whole-exome sequencing, were subjected to array comparative genomic hybridization analysis. We identified eight significantly mutated genes, of which six are well known tumour-associated genes (TP53, RB1, CDKN2A, PIK3CA, NOTCH1, NFE2L2), and two have not previously been described in ESCC (ADAM29 and FAM135B). Notably, FAM135B is identified as a novel cancer-implicated gene as assayed for its ability to promote malignancy of ESCC cells. Additionally, MIR548K, a microRNA encoded in the amplified 11q13.3-13.4 region, is characterized as a novel oncogene, and functional assays demonstrate that MIR548K enhances malignant phenotypes of ESCC cells. Moreover, we have found that several important histone regulator genes (MLL2 (also called KMT2D), ASH1L, MLL3 (KMT2C), SETD1B, CREBBP and EP300) are frequently altered in ESCC. Pathway assessment reveals that somatic aberrations are mainly involved in the Wnt, cell cycle and Notch pathways. Genomic analyses suggest that ESCC and head and neck squamous cell carcinoma share some common pathogenic mechanisms, and ESCC development is associated with alcohol drinking. This study has explored novel biological markers and tumorigenic pathways that would greatly improve therapeutic strategies for ESCC.

36A gene-environment-induced epigenetic program initiates tumorigenesis.PubMed

Direna Alonso-Curbelo, Yu-Jui Ho, Cassandra Burdziak, et al.
Nature. 2021 Feb;590(7847):642-648. doi: 10.1038/s41586-020-03147-x. Epub 2021 Feb 3.
Tissue damage increases the risk of cancer through poorly understood mechanisms. In mouse models of pancreatic cancer, pancreatitis associated with tissue injury collaborates with activating mutations in the Kras oncogene to markedly accelerate the formation of early neoplastic lesions and, ultimately, adenocarcinoma. Here, by integrating genomics, single-cell chromatin assays and spatiotemporally controlled functional perturbations in autochthonous mouse models, we show that the combination of Kras mutation and tissue damage promotes a unique chromatin state in the pancreatic epithelium that distinguishes neoplastic transformation from normal regeneration and is selected for throughout malignant evolution. This cancer-associated epigenetic state emerges within 48 hours of pancreatic injury, and involves an 'acinar-to-neoplasia' chromatin switch that contributes to the early dysregulation of genes that define human pancreatic cancer. Among the factors that are most rapidly activated after tissue damage in the pre-malignant pancreatic epithelium is the alarmin cytokine interleukin 33, which recapitulates the effects of injury in cooperating with mutant Kras to unleash the epigenetic remodelling program of early neoplasia and neoplastic transformation. Collectively, our study demonstrates how gene-environment interactions can rapidly produce gene-regulatory programs that dictate early neoplastic commitment, and provides a molecular framework for understanding the interplay between genetic and environmental cues in the initiation of cancer.

37Thinking Cancer.PubMed

Anastas Pashov, Cinthia Violeta Hernandez Puente, Saddam Mohammed Ibrahim, et al.
Monoclon Antib Immunodiagn Immunother. 2018 Jun;37(3):117-125. doi: 10.1089/mab.2018.0014.
Evolutionary theories are necessarily invoked for understanding cancer development at the level of species, at the level of cells and tissues, and for developing effective therapies. It is crucial to view cancer in a Darwinian light, where the differential survival of individual cells is based on heritable variations. In the process of this somatic evolution, multicellularity controls are overridden by cancer cells, which become increasingly autonomous. Ecological epigenetics also helps understand how rogue cells that have basically the same DNA as their normal cell counterpart overcome the tissue homeostasis. As we struggle to wrap our minds around the complexity of these phenomena, we apply often times anthropomorphic terms, such as subversion, hijacking, or hacking, to describe especially the most complex among them-the interaction of tumors with the immune system. In this commentary we highlight examples of the anthropomorphic thinking of cancer and try to put into context the relative meaning of terms and the mechanisms that are oftentimes invoked to justify those terms.

38Hereditary cancer predisposition syndromes.PubMed

Judy E Garber, Kenneth Offit
J Clin Oncol. 2005 Jan 10;23(2):276-92. doi: 10.1200/JCO.2005.10.042.
Cancer genetics is increasingly becoming integrated into the practice of modern medical oncology. The ability to distinguish a growing proportion of the 5% to 10% of all cancers that develop in individuals who have inherited a genetic mutation conferring heightened susceptibility to specific cancers may permit targeted efforts in cancer surveillance and prevention. While these individuals comprise a small proportion of the overall burden of cancer, strategies successful in reducing their remarkable cancer risks may be generalizable to the broader population. In this review, we highlight the most common hereditary cancer syndromes, most attributable to genes inherited in an autosomal dominant manner with incomplete penetrance, and a number of rare syndromes in which particular progress has been made. The prevalence, penetrance, tumor spectrum, and underlying genetic defects are discussed and summarized in a large table in which a more comprehensive enumeration of syndromes is provided.

39The BRCA1 and BRCA2 Genes in Early-Onset Breast Cancer Patients.PubMed

Mohamed Saleem, Mohd Bazli Ghazali, Md Azlan Mohamed Abdul Wahab, et al.
Adv Exp Med Biol. 2020;1292:1-12. doi: 10.1007/5584_2018_147.
Approximately 5-10% of breast cancers are attributable to genetic susceptibility. Mutations in the BRCA1 and BRCA2 genes are the best known genetic factors to date. The goal of this study was to determine the structure and distribution of haplotypes of the BRCA1 and BRCA2 genes in early-onset breast cancer patients. We enrolled 70 patients diagnosed with early-onset breast cancer. A total of 21 SNPs (11 on BRCA1 and 10 on BRCA2) and 1 dinucleotide deletion on BRCA1 were genotyped using nested allele-specific PCR methods. Linkage disequilibrium (LD) analysis was conducted, and haplotypes were deduced from the genotype data. Two tightly linked LD blocks were observed on each of the BRCA1 and BRCA2 genes. Variant-free haplotypes (TAT-AG for BRCA1 and ATA-AAT for BRCA2) were observed at a frequency of more than 50% on each gene along with variable frequencies of derived haplotypes. The variant 3'-subhaplotype CGC displayed strong LD with 5'-subhaplotypes GA, AA, and GG on BRCA1 gene. Haplotypes ATA-AGT, ATC-AAT, and ATA-AAC were the variant haplotypes frequent on BRCA2 gene. Although the clinical significance of these derived haplotypes has not yet been established, it is expected that some of these haplotypes, especially the less frequent subhaplotypes, eventually will be shown to be indicative of a predisposition to early-onset breast cancer.

40Frequency of germline genetic variants in women with a personal or family history of breast cancer from Brazil.PubMed

Júlia Zanon Pereira, Juliana Garcia Carneiro, Mariana Sousa Vieira, et al.
Mol Biol Rep. 2022 Oct;49(10):9509-9520. doi: 10.1007/s11033-022-07840-0. Epub 2022 Aug 18.
BACKGROUND: About 5-10% of breast cancer cases are related to genetic and hereditary factors. The application of Next Generation Sequencing (NGS) in oncology has allowed the identification of genetic variants present in several genes related to the increased risk of breast cancer. This study aimed to determine the frequency of germline genetic variants in patients with a family and/or personal history of breast cancer. METHODS: An analysis of positive reports from NGS panels was carried out in female individuals with a personal and/or family history of breast cancer, present in the database of a private laboratory in Brazil. RESULTS: From about 2000 reports, 183 individuals presented 219 different germline genetic variants. The genes with the highest number of variants were BRCA2 (16.0%), ATM (15.0%) and BRCA1 (12.8%). Among the variants found, 78 were either pathogenic or probably pathogenic, accounting for 35% of all variants discovered. The gene with the highest proportion of pathogenic/probably pathogenic variants was TP53 (80%) and the most frequent pathogenic variant was also reported in this gene (c.1010G > A p.(Arg337His)). Furthermore, the study obtained a high proportion of variants of uncertain significance (VUS) (65%) and approximately 32% of the variants found were in genes of moderate penetrance. CONCLUSIONS: Our results could improve the risk estimation and clinical follow-up of Brazilian patients with a history of breast cancer.

41Retinoblastoma.PubMed

Dietmar Lohmann
Adv Exp Med Biol. 2010;685:220-7. doi: 10.1007/978-1-4419-6448-9_21.
Retinoblastoma (Rb) is a malignant tumor that originates from developing retina. Diagnosis based on clinical signs and symptoms and is usually made in children under the age of five years. Mutations in both alleles of the RB1 gene are a prerequisite for this tumor to develop. In most patients with sporadic unilateral Rb, both RB1 gene mutations occur in somatic cells and are not passed over to offspring (nonhereditary Rb). Almost all patients with sporadic bilateral and virtually all patients with familial Rb are heterozygous for RB1 gene mutations that cause predisposition to Rb (hereditary Rb). In families, Rb predisposition is transmitted as an autosomal dominant trait (familial Rb). In addition to Rb, patients with hereditary disease also have an increased risk of tumors outside the eye (second cancer). This risk is enhanced in patients who have received external beam radiotherapy. Analysis of genotype-phenotype associations has shown that the mean number of tumor foci that develop in carriers of mutant RB1 alleles is variable depending on which functions of the normal allele are retained and to what extent. Moreover, phenotypic expression of hereditary retinoblastoma is subject to genetic modification. Identification of the genetic factors that underlie these effects will not only help to arrive at a more precise prognosis but may also point to mechanisms that can be used to reduce the risk of tumor development.

42Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma.PubMed

Koji Shindo, Jun Yu, Masaya Suenaga, et al.
J Clin Oncol. 2017 Oct 20;35(30):3382-3390. doi: 10.1200/JCO.2017.72.3502. Epub 2017 Aug 2.
Purpose Deleterious germline mutations contribute to pancreatic cancer susceptibility and are well documented in families in which multiple members have had pancreatic cancer. Methods To define the prevalence of these germline mutations in patients with apparently sporadic pancreatic cancer, we sequenced 32 genes, including known pancreatic cancer susceptibility genes, in DNA prepared from normal tissue obtained from 854 patients with pancreatic ductal adenocarcinoma, 288 patients with other pancreatic and periampullary neoplasms, and 51 patients with non-neoplastic diseases who underwent pancreatic resection at Johns Hopkins Hospital between 2000 and 2015. Results Thirty-three (3.9%; 95% CI, 3.0% to 5.8%) of 854 patients with pancreatic cancer had a deleterious germline mutation, 31 (3.5%) of which affected known familial pancreatic cancer susceptibility genes: BRCA2 (12 patients), ATM (10 patients), BRCA1 (3 patients), PALB2 (2 patients), MLH1 (2 patients), CDKN2A (1 patient), and TP53 (1 patient). Patients with these germline mutations were younger than those without (mean ± SD, 60.8 ± 10.6 v 65.1 ± 10.5 years; P = .03). Deleterious germline mutations were also found in BUB1B (1) and BUB3 (1). Only three of these 33 patients had reported a family history of pancreatic cancer, and most did not have a cancer family history to suggest an inherited cancer syndrome. Five (1.7%) of 288 patients with other periampullary neoplasms also had a deleterious germline mutation. Conclusion Germline mutations in pancreatic cancer susceptibility genes are commonly identified in patients with pancreatic cancer without a significant family history of cancer. These deleterious pancreatic cancer susceptibility gene mutations, some of which are therapeutically targetable, will be missed if current family history guidelines are the main criteria used to determine the appropriateness of gene testing.

43Prevalence of Germline Sequence Variations Among Patients With Pancreatic Cancer in China.PubMed

Lingdi Yin, Jishu Wei, Zipeng Lu, et al.
JAMA Netw Open. 2022 Feb 1;5(2):e2148721. doi: 10.1001/jamanetworkopen.2021.48721.
IMPORTANCE: A higher incidence of pancreatic cancer has been reported in the Chinese population compared with the White population, but genetic differences are unknown to date. Large-sample germline testing for both familial and sporadic pancreatic cancers has been conducted predominantly in White populations, whereas similar studies in Chinese populations are limited. OBJECTIVE: To assess the prevalence of germline sequence variations in patients with pancreatic diseases in China. DESIGN, SETTING, AND PARTICIPANTS: This genetic association study was a case series that included genetic data from patients with pancreatic ductal adenocarcinoma (PDAC) or non-PDAC pancreatic diseases seen at The First Affiliated Hospital of Nanjing Medical University in Nanjing, China, between January 2006 and December 2017 (Nanjing cohort). Comparator group data were obtained for a US cohort from Johns Hopkins Hospital (JHH), a population from East Asia from the Exome Aggregation Consortium (ExAC) database, and the larger population from China from the ChinaMAP database. Data were updated and analyzed in July 2021. MAIN OUTCOMES AND MEASURES: Next-generation sequencing technology was used to examine the prevalence of deleterious variations in 59 genes of the included Chinese patients with DNA extracted from peripheral blood samples. The Fisher exact test was used to assess differences among the frequencies of germline variations in the study patients vs the comparator groups. RESULTS: A total of 1009 patients with PDAC (627 [62.1%] male; mean [SD] age, 62.8 [10.2] years) and 885 with non-PDAC diseases (477 [53.9%] male; mean [SD] age, 52.0 [15.9] years) from the Nanjing cohort were included for genetic analysis; all were Han Chinese individuals. Pathogenic variations were detected in 63 patients with PDAC (6.2%; 95% CI, 4.7%-7.7%). Variations in BRCA2 (odds ratio [OR], 3.2; 95% CI, 1.4-7.7; P = .008) and PALB2 (OR, 5.2; 95% CI, 1.6-17.0; P = .007) were significantly associated with pancreatic risk in the Nanjing cohort. Pathogenic variants of genes associated with homologous recombination DNA damage repair, including ATM, BRCA1/2, PALB2, BRIP1, FANCA, FANCC, RAD51D, and XRCC2, were found in 34 patients with PDAC (3.4%). No Ashkenazi Jewish-specific BRCA2 variation (p.Ser1982fs) was detected. The odds ratio of a SPINK1 variation in patients with PDAC was 3.2 (95% CI, 1.8-5.7; P < .001) in the Nanjing cohort compared with the ExAC cohort. Variations in the pancreatic secretory enzyme genes CPA1 and CPB1 were not detected in the Nanjing cohort. CONCLUSIONS AND RELEVANCE: In this genetic association study, sporadic pancreatic cancer was associated with pathogenic germline variations in a cohort from China. These findings provide insights into the genetic background of pancreatic cancer in the Han Chinese population with PDAC.

44Investigation on factors associated with ovarian cancer: an umbrella review of systematic review and meta-analyses.PubMed

Kiarash Tanha, Azadeh Mottaghi, Marzieh Nojomi, et al.
J Ovarian Res. 2021 Nov 11;14(1):153. doi: 10.1186/s13048-021-00911-z.
Following cervical and uterine cancer, ovarian cancer (OC) has the third rank in gynecologic cancers. It often remains non-diagnosed until it spreads throughout the pelvis and abdomen. Identification of the most effective risk factors can help take prevention measures concerning OC. Therefore, the presented review aims to summarize the available studies on OC risk factors. A comprehensive systematic literature search was performed to identify all published systematic reviews and meta-analysis on associated factors with ovarian cancer. Web of Science, Cochrane Library databases, and Google Scholar were searched up to 17th January 2020. This study was performed according to Smith et al. methodology for conducting a systematic review of systematic reviews. Twenty-eight thousand sixty-two papers were initially retrieved from the electronic databases, among which 20,104 studies were screened. Two hundred seventy-seven articles met our inclusion criteria, 226 of which included in the meta-analysis. Most commonly reported genetic factors were MTHFR C677T (OR=1.077; 95 % CI (1.032, 1.124); P-value<0.001), BSML rs1544410 (OR=1.078; 95 %CI (1.024, 1.153); P-value=0.004), and Fokl rs2228570 (OR=1.123; 95 % CI (1.089, 1.157); P-value<0.001), which were significantly associated with increasing risk of ovarian cancer. Among the other factors, coffee intake (OR=1.106; 95 % CI (1.009, 1.211); P-value=0.030), hormone therapy (RR=1.057; 95 % CI (1.030, 1.400); P-value<0.001), hysterectomy (OR=0.863; 95 % CI (0.745, 0.999); P-value=0.049), and breast feeding (OR=0.719, 95 % CI (0.679, 0.762) and P-value<0.001) were mostly reported in studies. Among nutritional factors, coffee, egg, and fat intake significantly increase the risk of ovarian cancer. Estrogen, estrogen-progesterone, and overall hormone therapies also are related to the higher incidence of ovarian cancer. Some diseases, such as diabetes, endometriosis, and polycystic ovarian syndrome, as well as several genetic polymorphisms, cause a significant increase in ovarian cancer occurrence. Moreover, other factors, for instance, obesity, overweight, smoking, and perineal talc use, significantly increase the risk of ovarian cancer.

45Epidemiology of Bladder Cancer: A Systematic Review and Contemporary Update of Risk Factors in 2018.PubMed

Marcus George Kwesi Cumberbatch, Ibrahim Jubber, Peter C Black, et al.
Eur Urol. 2018 Dec;74(6):784-795. doi: 10.1016/j.eururo.2018.09.001. Epub 2018 Sep 26.
CONTEXT: Bladder cancer (BC) is a significant health problem, and understanding the risk factors for this disease could improve prevention and early detection. OBJECTIVE: To provide a systematic review and summary of novel developments in epidemiology and risk factors for BC. EVIDENCE ACQUISITION: A systematic review of original articles was performed by two pairs of reviewers (M.G.C., I.J., F.E., and K.P.) using PubMed/Medline in December 2017, updated in April 2018. To address our primary objective of reporting contemporary studies, we restricted our search to include studies from the last 5yr. We subdivided our review according to specific risk factors (PICO [Population Intervention Comparator Outcome]). EVIDENCE SYNTHESIS: Our search found 2191 articles, of which 279 full-text manuscripts were included. We separated our manuscripts by the specific risk factor they addressed (PICO). According to GLOBOCAN estimates, there were 430000 new BC cases and 165000 deaths worldwide in 2012. Tobacco smoking and occupational exposure to carcinogens remain the factors with the highest attributable risk. The literature was limited by heterogeneity of data. CONCLUSIONS: Evidence is emerging regarding gene-environment interactions, particularly for tobacco and occupational exposures. In some populations, incidence rates are declining, which may reflect a decrease in smoking. Standardisation of reporting may help improve epidemiologic evaluation of risk. PATIENT SUMMARY: Bladder cancer is common worldwide, and the main risk factors are tobacco smoking and exposure to certain chemicals in the working and general environments. There is ongoing research to identify and reduce risk factors, as well as to understand the impact of genetics on bladder cancer risk.

46Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland.PubMed

P Lichtenstein, N V Holm, P K Verkasalo, et al.
N Engl J Med. 2000 Jul 13;343(2):78-85. doi: 10.1056/NEJM200007133430201.
BACKGROUND: The contribution of hereditary factors to the causation of sporadic cancer is unclear. Studies of twins make it possible to estimate the overall contribution of inherited genes to the development of malignant diseases. METHODS: We combined data on 44,788 pairs of twins listed in the Swedish, Danish, and Finnish twin registries in order to assess the risks of cancer at 28 anatomical sites for the twins of persons with cancer. Statistical modeling was used to estimate the relative importance of heritable and environmental factors in causing cancer at 11 of those sites. RESULTS: At least one cancer occurred in 10,803 persons among 9512 pairs of twins. An increased risk was found among the twins of affected persons for stomach, colorectal, lung, breast, and prostate cancer. Statistically significant effects of heritable factors were observed for prostate cancer (42 percent; 95 percent confidence interval, 29 to 50 percent), colorectal cancer (35 percent; 95 percent confidence interval, 10 to 48 percent), and breast cancer (27 percent; 95 percent confidence interval, 4 to 41 percent). CONCLUSIONS: Inherited genetic factors make a minor contribution to susceptibility to most types of neoplasms. This finding indicates that the environment has the principal role in causing sporadic cancer. The relatively large effect of heritability in cancer at a few sites suggests major gaps in our knowledge of the genetics of cancer.

47Using epigenomic studies in monozygotic twins to improve our understanding of cancer.PubMed

Leonie Roos, Timothy D Spector, Christopher G Bell
Epigenomics. 2014 Jun;6(3):299-309. doi: 10.2217/epi.14.13.
Cancer is a set of diseases that exhibit not only genetic mutations but also a profoundly distorted epigenetic landscape. Over the last two decades, great advances have been made in identifying these alterations and their importance in the initiation and progression of cancer. Epigenetic changes can be seen from the very early stages in tumorigenesis and dysregulation of the epigenome has an increasingly acknowledged pathogenic role. Epigenomic twin studies have great potential to contribute to our understanding of complex diseases, such as cancer. This is because the use of monozygotic twins discordant for cancer enables epigenetic variation analysis without the confounding influence of the constitutive genetic background, age or cohort effects. It therefore allows the identification of susceptibility loci that may be sensitive to modification by the environment. These studies into cancer etiology will potentially lead to robust epigenetic markers for the detection and risk assessment of cancer.

48Impact of ambient air pollution on colorectal cancer risk and survival: insights from a prospective cohort and epigenetic Mendelian randomization study.PubMed

Fangyuan Jiang, Jianhui Zhao, Jing Sun, et al.
EBioMedicine. 2024 May;103:105126. doi: 10.1016/j.ebiom.2024.105126. Epub 2024 Apr 16.
BACKGROUND: This study investigates the associations between air pollution and colorectal cancer (CRC) risk and survival from an epigenomic perspective. METHODS: Using a newly developed Air Pollutants Exposure Score (APES), we utilized a prospective cohort study (UK Biobank) to investigate the associations of individual and combined air pollution exposures with CRC incidence and survival, followed by an up-to-date systematic review with meta-analysis to verify the associations. In epigenetic two-sample Mendelian randomization analyses, we examine the associations between genetically predicted DNA methylation related to air pollution and CRC risk. Further genetic colocalization and gene-environment interaction analyses provided different insights to disentangle pathogenic effects of air pollution via epigenetic modification. FINDINGS: During a median 12.97-year follow-up, 5767 incident CRC cases among 428,632 participants free of baseline CRC and 533 deaths in 2401 patients with CRC were documented in the UK Biobank. A higher APES score was associated with an increased CRC risk (HR, 1.03, 95% CI = 1.01-1.06; P = 0.016) and poorer survival (HR, 1.13, 95% CI = 1.03-1.23; P = 0.010), particularly among participants with insufficient physical activity and ever smokers (P > 0.05). A subsequent meta-analysis of seven observational studies, including UK Biobank data, corroborated the association between PM exposure (per 10 μg/m increment) and elevated CRC risk (RR,1.42, 95% CI = 1.12-1.79; P = 0.004; I = 90.8%). Genetically predicted methylation at PM-related CpG site cg13835894 near TMBIM1/PNKD and cg16235962 near CXCR5, and NO-related cg16947394 near TMEM110 were associated with an increased CRC risk. Gene-environment interaction analysis confirmed the epigenetic modification of aforementioned CpG sites with CRC risk and survival. INTERPRETATION: Our study suggests the association between air pollution and CRC incidence and survival, underscoring the possible modifying roles of epigenomic factors. Methylation may partly mediate pathogenic effects of air pollution on CRC, with annotation to epigenetic alterations in protein-coding genes TMBIM1/PNKD, CXCR5 and TMEM110. FUNDING: Xue Li is supported by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001), the National Nature Science Foundation of China (No. 82204019) and Healthy Zhejiang One Million People Cohort (K-20230085). ET is supported by a Cancer Research UK Career Development Fellowship (C31250/A22804). MGD is supported by the MRC Human Genetics Unit Centre Grant (U127527198).

49Genetic evaluation procedures at sperm banks in the United States.PubMed

Lauren Isley, Pamela Callum
Fertil Steril. 2013 May;99(6):1587-91. doi: 10.1016/j.fertnstert.2013.01.093. Epub 2013 Feb 5.
OBJECTIVE: To assess how genetic evaluations of sperm donor applicants are performed in the United States. DESIGN: A questionnaire was designed to assess: 1) the professionals involved in the family history evaluation and genetic screening; 2) the genetic testing, counseling, and informed consent processes; and 3) how the results of genetic evaluations and new risk information is communicated to donors. SETTING: Semen donor facilities. PARTICIPANT(S): Representatives of semen donor facilities. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Descriptive data. RESULT(S): Thirteen responses were received. All of the facilities assessed donors' family histories; eight of the facilities (62%) routinely informed donors about the results of these evaluations. At the majority of facilities (10/13), informed consent for genetic testing is obtained as part of the overall contract to be a sperm donor. Genetic counselors are employed full-time at two facilities and part-time at five others. CONCLUSION(S): There is variability in the education and informed consent processes for semen donor applicants, including variable communication about the limitations of genetic tests and the potential implications for the donors' own children. Further research into the best practices for education and consent for sperm donor applicants may be beneficial to ensure the well-being of the donors and their future offspring.

50Discrepancies between application and genetic consultation during routine ovum donor screening in large fertility network.PubMed

Camelia Varriale, Laurel Anderson, Emily Daugherty, et al.
J Assist Reprod Genet. 2025 Nov;42(11):3809-3815. doi: 10.1007/s10815-025-03672-6. Epub 2025 Sep 19.
PURPOSE: To compare the personal and family medical history information obtained from a written application to a formal genetic risk assessment performed in consultation with a certified genetic counselor, as well as categorize and qualify any discrepant information. METHODS: This was a retrospective cohort study of female subjects applying to become deidentified ovum donors, between ages 21 and 31 and who were determined to be eligible candidates with initial application and interview. Information provided by prospective ovum donors in their self-reported written application was compared to their genetic risk assessment performed in consultation with a certified genetic counselor, which documents family demographics and health history for a minimum of three generations. Discrepancies were categorized as relating to a health change or no health change (demographic) and then grouped by number of changes. Demographic changes included ages, number of family members, and age at time of death. Health changes were any new information relating to a health condition in prospective ovum donors and/or any family members. RESULT(S): A total of 600 randomly selected ovum donor applications and the associated genetic risk assessments were compared; 84% of these applicants reported novel health information during the genetic risk assessment. Of the total 600, 19% no longer met American Society of Reproductive Medicine (ASRM) or internal program guidelines for eligibility. CONCLUSIONS: Genetic risk assessment performed by a certified genetic counselor provides a more comprehensive representation of personal and family medical history and accurate assessment of the eligibility of an ovum donor compared to self-reported information alone.

51Preimplantation genetic testing for a chr14q32 microdeletion in a family with Kagami-Ogata syndrome and Temple syndrome.PubMed

Joan Sabria-Back, Ana Monteagudo-Sánchez, Marta Sánchez-Delgado, et al.
J Med Genet. 2022 Mar;59(3):253-261. doi: 10.1136/jmedgenet-2020-107433. Epub 2021 Feb 12.
INTRODUCTION: Kagami-Ogata syndrome (KOS14) and Temple syndrome (TS14) are two disorders associated with reciprocal alterations within the chr14q32 imprinted domain. Here, we present a work-up strategy for preimplantation genetic testing (PGT) to avoid the transmission of a causative micro-deletion. METHODS: We analysed DNA from the KOS14 index case and parents using methylation-sensitive ligation-mediated probe amplification and methylation pyrosequencing. The extent of the deletion was mapped using SNP arrays. PGT was performed in trophectoderm samples in order to identify unaffected embryos. Samples were amplified using multiple displacement amplification, followed by genome-wide SNP genotyping to determine the at-risk haplotype and next-generation sequencing to determine aneuploidies. RESULTS: A fully methylated pattern at the normally paternally methylated IG-DMR and DMR in the KOS14 proband, accompanied by an unmethylated profile in the TS14 mother was consistent with maternal and paternal transmission of a deletion, respectively. Further analysis revealed a 108 kb deletion in both cases. The inheritance of the deletion on different parental alleles was consistent with the opposing phenotypes. In vitro fertilisation with intracytoplasmatic sperm injection and PGT were used to screen for deletion status and to transfer an unaffected embryo in this couple. A single euploid-unaffected embryo was identified resulting in a healthy baby born. DISCUSSION: We identify a microdeletion responsible for multigeneration KOS14 and TS14 within a single family where carriers have a 50% risk of transmitting the deletion to their offspring. We show that PGT can successfully be offered to couples with IDs caused by genetic anomalies.

52Analysis of human sperm karyotypes in testicular cancer patients before and after chemotherapy.PubMed

R H Martin, S Ernst, A Rademaker, et al.
Cytogenet Cell Genet. 1997;78(2):120-3. doi: 10.1159/000134642.
Sperm karyotype analysis was performed on testicular cancer patients before and after treatment with BEP (bleomycin, etoposide, and cisplatin). A total of 788 sperm chromosome complements was studied, 236 before chemotherapy (CT) and 552 post-CT. There was no significant difference in the total frequency of sperm chromosomal abnormalities pre-CT (10.2%) compared to post-CT (10.7%). Similarly, there were no significant differences in the frequencies of numerical abnormalities (2.5% pre-CT vs. 2.4% post-CT) or structural abnormalities (6.4% pre-CT vs. 7.4% post-CT). The percentage of X-bearing sperm was also not significantly different before (46.3%) and after CT (50.1%). The results in cancer patients were not significantly different from those in control donors. This study corroborates results from our previous analysis of these same men using multicolor fluorescence in situ hybridization for assessment of aneuploidy for chromosomes 1, 12, X, Y, and XY. Together, these two studies suggest that the sperm of men receiving BEP chemotherapy are not at increased risk of chromosomal abnormalities two or more years after treatment.

53Human sperm chromosome complements in chemotherapy patients and infertile men.PubMed

R Martin
Chromosoma. 1998 Dec;107(6-7):523-7. doi: 10.1007/s004120050338.
Our studies of human sperm karyotypes and interphase sperm analyzed by fluorescence in situ hybridization (FISH) have both yielded estimates of disomy frequencies of approximately 0.1% per chromosome with an overall aneuploidy frequency in human sperm of approximately 5%-6%. However, the distribution of aneuploidy in sperm is not even, as our data from sperm karyotypes and multicolour FISH analyses both demonstrate a significant increase in the frequency of aneuploidy for chromosome 21 and the sex chromosomes. We have studied men at increased risk of sperm chromosomal abnormalities including cancer patients and infertility patients. Testicular cancer patients were studied before and 2-13 years after chemotherapy (CT) with BEP (bleomycin, etoposide, cisplatin). Sperm karyotype analysis on 788 sperm demonstrated no significant difference in the frequency of numerical or structural chromosomal abnormalities post-CT vs pre-CT. Similarly, multicolour FISH analysis for chromosomes 1, 12, XX, YY and XY in 161,097 sperm did not detect any significant differences in the frequencies of disomy before and after treatment. However, recent evidence has suggested a significant increase in the frequency of disomy and diploidy during CT. We have found that infertile men, who would be candidates for intracytoplasmic sperm injection, have an increased frequency of chromosomally abnormal sperm karyotypes. Also, FISH analysis for chromosomes 1, 12, 13, 21, XX, YY and XY in 255,613 sperm demonstrated a significant increase in chromosomes 1, 13, 21, and XY disomy in infertile men compared with control donors.

54Turner syndrome: fertility, familial clustering, and cancer risk.PubMed

K Allen-Brady, L E Verrilli, B A Austin, et al.
Hum Reprod. 2025 Feb 1;40(2):391-396. doi: 10.1093/humrep/deae266.
STUDY QUESTION: Is there an increased risk of reproductive or colon cancer in women with Turner syndrome and their family members? SUMMARY ANSWER: Our data suggest that there is an increased risk for sigmoid colon cancer in women with Turner syndrome and an increased prostate cancer risk in second- and third-degree male relatives. WHAT IS KNOWN ALREADY: Turner syndrome has been associated with lower risk of breast cancer, but increased risk of gonadoblastoma and colon cancer in some, but not all studies. There is also evidence for a genetic predisposition to sex chromosome aneuploidy, which may indicate a predisposition to Turner syndrome and the associated cancer risk in family members. STUDY DESIGN, SIZE, DURATION: The study was a retrospective case-control study of women with Turner syndrome diagnosed from 1995 to 2021, their relatives, and population subjects from Utah. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with Turner syndrome were identified using International Classification of Disease (ICD) codes in electronic medical records from two major Utah healthcare systems and reviewed for accuracy. Women with Turner syndrome were linked to genealogy in the Utah Population Database. Cancer diagnoses (breast, ovarian, endometrial, colon, testicular, and prostate) were determined for women with Turner syndrome and their relatives using the Utah Cancer Registry. Live births to women with Turner syndrome were identified by linked birth certificates. The relative risk of cancer in women with Turner syndrome and in relatives was estimated by comparison to population rates matched by age, sex, and birthplace. MAIN RESULTS AND THE ROLE OF CHANCE: We identified 289 women with Turner syndrome. Sigmoid colon cancer was increased in women with Turner syndrome (OR [95% CI] 24.2 [2.9, 87.4]; P = 0.0032). There were 233 women with Turner syndrome who had at least three generations of genealogical data. There was an increased risk of Turner syndrome in first- (OR [95% CI] 18.08 [2.19, 65.32]; P = 0.0057) and second-degree relatives (9.62 [1.17, 34.74]; P = 0.019), although numbers were very small. There was an increased risk of prostate cancer in second- (1.8 [1.4, 2.2]; P < 0.001) and third-degree relatives (1.3 [1.1, 1.5]; P < 0.001). There was no increased risk of colon cancer in relatives. LIMITATIONS, REASONS FOR CAUTION: Based on the small number of sigmoid colon cancer cases, it is possible that our data have overestimated the colon cancer risk. Limitations include the identification of Turner syndrome by a diagnosis code in one of the two major health systems in Utah. The population is largely northern European with 9.3% of the women self-identified as Hispanic and 2.4% as Native American or multiple races. The results may not be generalizable to other populations. WIDER IMPLICATIONS OF THE FINDINGS: Our data suggest that women with Turner syndrome may need early screening for colon cancer. Additional studies are needed to identify risk factors for sex chromosome aneuploidy and cancer risk in women with Turner syndrome and their male relatives. STUDY FUNDING/COMPETING INTEREST(S): The work in this publication was supported by R56HD090159 and R01HD099487 (C.K.W.). We also acknowledge partial support for the Utah Population Database through grant P30 CA2014 from the National Cancer Institute. The Utah Cancer Registry is funded by the National Cancer Institute's SEER Program, Contract No. HHSN261201800016I, the US Centers for Disease Control and Prevention's National Program of Cancer Registries, Cooperative Agreement No. NU58DP007131, with additional support from the University of Utah and Huntsman Cancer Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

55Clinical exome sequencing for carrier screening in assisted reproductive technology and sperm donation.PubMed

He Cai, Haiyan Bai, Sen Qiao, et al.
J Assist Reprod Genet. 2025 Apr;42(4):1247-1256. doi: 10.1007/s10815-025-03406-8. Epub 2025 Jan 30.
PURPOSE: To assess the efficacy of clinical exome sequencing (CES) in individuals involved in assisted reproductive technology (ART) or sperm donor programs, with a specific focus on its impact on clinical decision-making. METHODS: A total of 3991 individuals without a family history of genetic disorders underwent CES targeting 5595 genes at a reproductive center between December 2022 and April 2024. The cohort comprised 217 sperm donors, 232 female recipients, and 1771 couples (3542 patients) undergoing ART with their own gametes. At-risk couples (ARCs) were identified when both partners had a pathogenic or likely pathogenic variant (P/LP) in the same autosomal recessive gene or X-linked variants in females. The analysis primarily examined carrier frequencies, reproductive choices, and outcomes of ARCs. RESULTS: Among the 3991 individuals screened, 3895 (97.6%) were found to carry at least one P/LP variant, with an average carrier burden of 3.8 variants per individual, showing no significant disparity in carrier status between individuals with infertility and sperm donors/recipients. Within the screened couples, 9.3% were identified as ARCs and 2.3% opted for preimplantation genetic testing for monogenic diseases (PGT-M). As of now, 31 ARCs proceeded with the transfer of euploid and unaffected blastocysts, resulting in 8 healthy live births and 13 ongoing pregnancies. CONCLUSION: The findings reveal a significant prevalence of carrier status for autosomal recessive and X-linked diseases, irrespective of fertility status. This highlights the critical importance of integrating genetic risk counseling and informed reproductive decision-making into fertility clinics and sperm banks.

56PRDX5 and PRDX6 translocation and oligomerization in bull sperm: a response to cryopreservation-induced oxidative stress.PubMed

Mostek-Majewska Agnieszka, Bossowska-Nowicka Magdalena, Słowińska Mariola, et al.
Cell Commun Signal. 2025 Jan 9;23(1):15. doi: 10.1186/s12964-024-02015-9.
Cryopreservation of bull sperm, crucial for breeding and assisted reproduction, often reduces sperm quality due to oxidative stress. This study examines how oxidative stress during cryopreservation affects peroxiredoxin 5 (PRDX5) and peroxiredoxin 6 (PRDX6) proteins, leading to their translocation and oligomerization in bull sperm. Increased reactive oxygen species (ROS) and nitric oxide (NO) levels were linked to reduced mitochondrial potential, higher DNA fragmentation, and increased membrane fluidity, prompting PRDX5 to move intracellularly and PRDX6 to the cell membrane. Under cryopreservation, these proteins formed high molecular weight oligomers, that may shift from peroxidase to chaperone roles. Their interaction with Toll-like receptor 4 (TLR4) may be key to their intracellular transport. On the other hand, the presence of PRDX5 and PRDX6 in exosomal vesicles suggested a potential mechanism for their transport into sperm cells. Using Imaging Flow Cytometry and various PAGE techniques, the study detected PRDX5 and PRDX6 in different sperm locations and analyzed their oligomer formation. These findings highlight the adaptive roles of PRDX5 and PRDX6 in protecting sperm cells, offering insights that could improve cryopreservation protocols in animal breeding and human reproductive medicine, and advance our understanding of the oxidative stress response in sperm cells.

57Polygenic risk scores and embryonic screening: considerations for regulation.PubMed

Casey M Haining, Julian Savulescu, Louise Keogh, et al.
J Med Ethics. 2025 Sep 22;51(10):719-728. doi: 10.1136/jme-2024-110145.
Polygenic risk scores (PRSs) have recently been used to inform reproductive decision-making in the context of embryonic screening. While this is yet to be widespread, it is contested and raises several challenges. This article provides an overview of some of the ethical considerations that arise with using PRSs for embryo screening and offers a series of regulatory considerations for jurisdictions that may wish to permit this in the future. These regulatory considerations cover possible regulators and regulatory tools, eligibility criteria, information and education requirements and the need for ongoing refinement of the relevant technology, research and consultation.

58Fluorescent enzyme-based biosensor for sensitive analysis of DNA damage in cryopreserved sperm.PubMed

Yue Zhou, Juan Wang, Lifan Zhuo, et al.
Cryobiology. 2023 Dec;113:104591. doi: 10.1016/j.cryobiol.2023.104591. Epub 2023 Oct 5.
The freeze-thaw process can induce irreversible structural and functional changes in human sperm, particularly sperm DNA damage. Selecting a more accurate and sensitive detection method for evaluating sperm DNA integrity is crucial. To accurately assess sperm DNA integrity following the freeze-thaw process and significantly improve the clinical and scientific utilization of cryopreserved sperm. In this study, we utilized a novel fluorescent biosensor, assisted by terminal deoxynucleotidyl transferase (TdT) and Endonuclease IV, to detect DNA breakpoints during sperm cryopreservation. We evaluated the biosensor's performance by comparing it with the conventional DNA fragmentation index (DFI) measured using sperm chromatin structure analysis (SCSA). The cryopreserved group exhibited a significantly higher sperm DFI compared to the fresh group. No significant difference was observed between the antioxidant group and the cryopreserved group. However, the new method revealed a significant reduction in the number of DNA breakpoints in the antioxidant group compared to the cryopreserved group. The novel biosensor demonstrated superior accuracy and effectiveness in assessing sperm DNA integrity during cryopreservation compared to the conventional SCSA method. We believe that the biosensor holds significant potential for widespread use in the field of reproductive medicine.

59TdT/Cas12a-based biosensor for sensitive detection of DNA breakpoints in sperm cryopreservation.PubMed

Bianbian Gao, Ziyang Liu, Bei Yan, et al.
Sci Rep. 2025 Jul 13;15(1):25297. doi: 10.1038/s41598-025-09768-4.
With the advancement of assisted reproductive technology (ART), sperm cryopreservation has become an essential technique in both clinical and research applications. However, maintaining DNA integrity during the freezing and thawing process remains a significant challenge. This study introduces an innovative TdT/Cas12a-based biosensor to enable precise detection and quantification of sperm DNA breakages. Compared to traditional methods such as the sperm chromatin structure assay (SCSA), this biosensor exhibits exceptional sensitivity (capable of detecting DNA breakages at as low as 0.001 nM) and molecular-level resolution, allowing for the precise localization and quantification of DNA breakpoints. By integrating TdT for nucleotide labeling and Cas12a for signal amplification, the system achieves high specificity and reliability. Additionally, the introduction of a standard strand as a quality control significantly enhances reproducibility. Furthermore, the study explores the protective effects of natural antioxidants on sperm DNA integrity during the freeze-thaw process. The results reveal a marked increase in DNA breakpoints caused by cryopreservation, with the TdT/Cas12a system outperforming traditional methods in providing detailed and accurate assessments. Notably, the addition of antioxidants effectively mitigates DNA damage during the freeze-thaw process, safeguarding sperm DNA integrity. This platform not only represents a significant advancement in DNA damage detection and monitoring but also supports the optimization of cryopreservation protocols and contributes to improving the success and safety of ART. It offers valuable insights and innovative tools for the field of reproductive medicine.

60The application of mean number of DNA breakpoints in sperm cryopreservation.PubMed

Bei Yan, Juan Wang, Yue Zhou, et al.
Cryobiology. 2024 Sep;116:104937. doi: 10.1016/j.cryobiol.2024.104937. Epub 2024 Jul 8.
Growing concerns over declining male semen quality and rising infertility have shifted attention to male fertility. Sperm cryopreservation emerges as a crucial tool in preserving male fertility, especially for patients who need proactive preservation, such as cancer patients before undergoing radiation or chemotherapy. Although cryopreservation does not directly address infertility, effective preservation can support future fertility. However, the process may compromise sperm DNA integrity. Despite their impairment, damaged sperm often retain vitality and may still have the potential to fertilize an egg. Nonetheless, if damaged sperm fertilize an egg, excessive DNA damage could impede embryo implantation and development, despite the egg's repair capabilities. Consequently, precise detection of sperm DNA damage is crucial and urgent. To better address the issue of sperm DNA damage detection, we have introduced a novel fluorescence biosensor technology known as the TDT/SD Probe. This technology utilizes terminal deoxynucleotidyl transferase (TdT) and strand displacement probes to accurately detect the number of sperm DNA breakage points during the cryopreservation process. Experimental results reveal that the number of sperm DNA breakpoints significantly increases after both sperm vitrification (8.17 × 10) and conventional slow freezing (10.80 × 10), compared to the DNA breakpoints of fresh semen samples (5.19 × 10). However, sperm vitrification has the least impact on sperm breakage points. This research provides innovative means for further optimizing sperm preservation techniques by offering a novel DNA damage detection method, enabling more precise assessment of sperm DNA damage during the freezing process.

61Experiences and attitudes of Danish men who were sperm donors more than 10 years ago; a qualitative interview study.PubMed

Stina Lou, Stina Bollerup, Morten Deleuran Terkildsen, et al.
PLoS One. 2023 Feb 15;18(2):e0281022. doi: 10.1371/journal.pone.0281022. eCollection 2023.
BACKGROUND: More knowledge about the long-term impact of sperm donation is essential as the donor's attitude towards donation may change over time. Personal and social developments may prompt a rethinking of previous actions and decisions, or even regret. Thus, the aim of this study was to explore the experiences and attitudes of men who were sperm donors more than 10 years ago. METHODS: From May to September 2021, semi-structured, qualitative interviews were conducted with 23 former donors (> 10 years since last donation) from Cryos International sperm bank. Two participants were non-anonymous donors and 21 were anonymous. The interviews were conducted by phone or via video (mean 24 minutes). All interviews were recorded, transcribed verbatim and rendered anonymous. Data were analyzed using thematic analysis. RESULTS: The analysis showed that most men had been donors for monetary and altruistic purposes, and now considered sperm donation as a closed chapter that was 'unproblematic and in the past'. Most men valued anonymity and emphasized the non-relatedness between donor and donor conceived offspring. Knowledge about recipients and donor offspring was seen as 'damaging' as it could create unwanted feelings of relatedness and responsibility towards them. All men acknowledged donor conceived persons' potential interests in knowing about their genetic heritage in order to understand appearance and personal traits, but also emphasized the donors' rights to anonymity. Potential breach of anonymity was generally considered 'highly problematic' as it was expected to disturb their families and force a relationship on them. CONCLUSION: This study reports on former donors who might not have volunteered for research due to lack of interest or protection of privacy. The majority of men valued anonymity and clearly demarcated a line between sperm donation and fatherhood, which was enforced by not knowing about the donor offspring or recipients.

62[Understanding of and attitude towards sperm donation among males in Shandong Province and their influencing factors and countermeasures].PubMed

Shi-hui Liu, Li Wang, Xiao-hui Song, et al.
Zhonghua Nan Ke Xue. 2016 Apr;22(4):315-9.
OBJECTIVE: To investigate the understanding of and attitude towards sperm donation among males of the right age in Shandong Province a provide some reference for improving the propaganda for sperm donation and the recruitment of sperm donors. METHODS: We conducted a questionnaire survey among the male students and other men of the right age for sperm donation in the three cities of Shandong Province, Jinan, Qingdao and Yantai, with the questionnaires distributed randomly and filled in anonymously on the spot. Then we performed statistical analysis on the 2 000 valid copies collected. RESULTS: Among the 2 000 males, only 227(11. 35%) accepted sperm donation,997(49. 85%) knew that sperm donation was harmless to health, and merely 9. 95% had donated or considered donating sperm. The misgivings about sperm donation mainly included possible ethical problems, personal privacy, the complicated procedure, and high requirements. CONCLUSION: Most males of the right age have misgivings about sperm donation. The propaganda for sperm donation in Shandong human sperm banks are relatively monotonous and needs to be improved.

63A Systematic Review of Qualitative Studies Investigating Motives and Experiences of Recipients of Anonymous Gamete Donation.PubMed

Tobias Bauer
Front Sociol. 2022 Feb 16;7:746847. doi: 10.3389/fsoc.2022.746847. eCollection 2022.
The decision to use an anonymous gamete donation in fertility treatment could have significant long-term psychological and social effects for all stakeholders involved. In light of the growing recognition of donor-conceived children's right to know their genetic parentage, this entails profound ethical implications. This review aims to carve out the full spectrum of recipients' motives and experiences related to donor anonymity which could serve as an analytical framework for future ethical and sociological research on issues of donor anonymity. This review was conducted following a seven-step approach for systematic reviews of empirical bioethics literature. The characteristics and quality of the studies included in this review were reported. Data analysis was conducted using qualitative content analysis and was informed by sociological functionalist theorizations of ignorance. The 53 studies selected showed a diverse spectrum of characteristics concerning date and country of study, methodology, family type of participants, sample size, and the timing of data collection in relation to the stage of treatment. A total of 22 categories of motives and experiences of recipients concerning donor anonymity were identified inductively and grouped into five main categories. Donor anonymity was identified as a eufunctional form of ignorance, by which the recipients experienced or intended to control, regulate, or protect inter-stakeholder relations. Interpreting recipients' motives and experiences concerning donor anonymity as a form of ignorance directed toward particular stakeholders helps reframe the discourse on donor anonymity. It is a fruitful approach that can be refined further and applied in future research. This review identified possible directions for future investigations on motives for donor anonymity: the need for more thorough inquiries into the change in recipients' preferences over time, such as in the form of longitudinal studies and research on the perspective of non-biological parents.

64Gamete donation: parents' experiences of searching for their child's donor siblings and donor.PubMed

T Freeman, V Jadva, W Kramer, et al.
Hum Reprod. 2009 Mar;24(3):505-16. doi: 10.1093/humrep/den469.
BACKGROUND: This study investigates the new phenomenon of parents of donor offspring searching for and contacting their child's 'donor siblings' (i.e. donor offspring conceived by the same donor) and donor. METHODS: Online questionnaires were completed by 791 parents (39% lone-mother, 35% lesbian-couple, 21% heterosexual-couple, 5% non-specified) recruited via the Donor Sibling Registry; a US-based international registry that facilitates contact between donor conception families who share the same donor. Data were collected on parents' reasons for searching for their child's donor siblings and/or donor, the outcome of these searches and parents' and their child's experiences of any resulting contact. RESULTS: Parents' principal motivation for searching for their child's donor siblings was curiosity and for their donor, enhancing their child's sense of identity. Some parents had discovered large numbers of donor siblings (maximum = 55). Most parents reported positive experiences of contacting and meeting their child's donor siblings and donor. CONCLUSIONS: This study highlights that having access to information about a child's donor origins is important for some parents and has potentially positive consequences. These findings have wider implications because the removal of donor anonymity in the UK and elsewhere means that increasing numbers of donor offspring are likely to seek contact with their donor relations in the future.

65Offspring searching for their sperm donors: how family type shapes the process.PubMed

D R Beeson, P K Jennings, W Kramer
Hum Reprod. 2011 Sep;26(9):2415-24. doi: 10.1093/humrep/der202. Epub 2011 Jun 26.
BACKGROUND: This study examines the findings from the largest survey to date of donor-inseminated (DI) offspring and focuses on respondents' learning of the method of their conception and their desire to contact their donor. METHODS: Online questionnaires were completed by 741 DI offspring, of whom 61.8% have heterosexual parents and 38.2% have lesbian parents. Respondents were recruited via the Donor Sibling Registry, a non-profit US-based international registry that facilitates communication between donor-conceived offspring and their non-biological and biological relatives. Data were collected on family composition, offspring's feelings regarding the method of their conception, communication within families, donor anonymity and their search for their donors. This investigation focuses on the relationship between family type (single or dual-parent and lesbian or heterosexual parent/s) and offspring's reactions to learning of their DI conception. RESULTS: Offspring of lesbian parents learned of their DI origins at earlier ages than offspring of heterosexual parents. In the latter families, disclosure tended to occur earlier in single-parent than in dual-parent families. Disclosure was most likely to be confusing to offspring of heterosexual parents, particularly when it occurred at an older age. The vast majority of offspring in all types of families desired contact with their donor; however, comfort in expressing curiosity regarding one's donor was lowest in dual-parent heterosexual families, with about one-quarter reporting an inability to discuss their origins with their social father. CONCLUSIONS: Although the findings are not based on a random sample, the desire among offspring surveyed here is for greater openness and contact with their donor. A variety of strategies are needed for offspring of heterosexual couples to benefit optimally from the general trend toward openness in gamete donation.

66The right to know genetic origins: a harmful value.PubMed

Kimberly Leighton
Hastings Cent Rep. 2014 Jul-Aug;44(4):5-6. doi: 10.1002/hast.334.

67The management of genetic origins: secrecy and openness in donor assisted conception in Israel and elsewhere.PubMed

R Landau
Hum Reprod. 1998 Nov;13(11):3268-73. doi: 10.1093/humrep/13.11.3268.
Donor assisted conception provides new opportunities for achieving parenthood but at the same time raises issues of secrecy, anonymity, and the management of the offspring's genetic origins. As with adoption, the child's right to a genetic identity is at stake. The first part of this paper examines bio-psychosocial evidence indicating that maintaining secrecy and anonymity regarding genetic parents may be detrimental to the well-being of the donor offspring, the donor, and the nurturing, social parents. The second part discusses different approaches to the disclosure of genetic origins. The third part presents the case of Israel, as reflected mainly in the Report of the Israeli Ministry of Justice (1994). The paper shows that the Committee, yielding to the medical profession in the country, preferred the interests of the adults involved in donor assisted conception to those of the offspring and made no sincere attempts to protect the child's basic right to genetic identity. In doing so, it turned its back on the well established policy of openness in the field of adoption and on the emerging trend to similar openness in donor assisted conception in other countries.

68Practical and ethical considerations when sperm donors die.PubMed

Guido Pennings
Andrology. 2025 Mar;13(3):573-576. doi: 10.1111/andr.13679. Epub 2024 Jul 2.
This paper considers the practical and ethical issues related to the death of a sperm donor. It looks at whether sperm banks should check whether the donor is alive at the time the spermatozoa is made available. Knowing that the donor has died in combination with the cause of death can provide important medical information but the chance is very small. However, when the information is available, it may help to decide whether to tell previous recipients and/or to block the remaining samples for future use. A second advantage may be that the donor's offspring can be informed that contact will not be possible and that recipients who are planning to order spermatozoa from an identity-release donor can be told that the donor has died. However, these advantages presume that identifiable equals contactable while there is no strict link between these two conditions.

69Attitudes of sperm, egg and embryo donors and recipients towards genetic information and screening of donors.PubMed

David J Amor, Annabelle Kerr, Nandini Somanathan, et al.
Reprod Health. 2018 Feb 9;15(1):26. doi: 10.1186/s12978-018-0468-9.
BACKGROUND: Gamete and embryo donors undergo genetic screening procedures in order to maximise the health of donor-conceived offspring. In the era of genomic medicine, expanded genetic screening may be offered to donors for the purpose of avoiding transmission of harmful genetic mutations. The objective of this study was to explore the attitudes of donors and recipients toward the expanded genetic screening of donors. METHODS: Qualitative interview study with thematic analysis, undertaken in a tertiary fertility centre. Semi-structured in-depth qualitative interviews were conducted with eleven recipients and nine donors from three different cohorts (sperm, egg and embryo donors/recipients). RESULTS: Donors and recipients acknowledged the importance of genetic information and were comfortable with the existing level of genetic screening of donors. Recipients recognised some potential benefits of expanded genetic screening of donors; however both recipients and donors were apprehensive about extended genomic technologies, with concerns about how this information would be used and the ethics of genetic selectivity. CONCLUSION: Participants in donor programs support some level of genetic screening of donors, but are wary of expanding genetic screening beyond current levels.

70Using the theory of planned behavior to predict parents' disclosure of donor conception to their children: a longitudinal study.PubMed

Johan Paulin, Kimmo Sorjonen, Gunilla Sydsjö, et al.
Hum Reprod. 2024 Jun 3;39(6):1247-1255. doi: 10.1093/humrep/deae070.
STUDY QUESTION: Can the application of the theory of planned behavior (TPB) help predict heterosexual parents' disclosure of donor conception to their children? SUMMARY ANSWER: Parents with a stronger will to act in accordance with social norms favoring disclosure were more likely to start the disclosure process within the next 5-9 years. WHAT IS KNOWN ALREADY: In contrast to single mothers by choice and same-sex couples, heterosexual couples need to make an active decision to disclose their use of donor conception to their child. While disclosure at an early age is encouraged by international guidelines, many heterosexual-couple parents struggle with this. A previous study has found an association between parental scores of TPB factors and disclosure intention, but so far, no study has applied the TPB to predict parents' disclosure behavior. STUDY DESIGN, SIZE, DURATION: The present study is based on the fourth and fifth waves of data collection (T4 and T5) in a nation-wide longitudinal study. Participating parents had conceived through identity-release oocyte donation (n = 68, response rate 65%) and sperm donation (n = 62, response rate 56%) as part of a heterosexual couple. PARTICIPANTS/MATERIALS, SETTING, METHODS: The present study is part of the prospective longitudinal Swedish Study on Gamete Donation (SSGD). Consecutive recruitment of couples starting oocyte or sperm donation treatment was conducted at all seven fertility clinics providing gamete donation in Sweden during a 3-year period (2005-2008). Participants were requested to complete postal surveys at five time points. The present study includes heterosexual-couple parents following oocyte or sperm donation who participated at the two latest time points when their children were 7-8 years old (T4), and 13-17 years old (T5). At T4, participants completed the study-specific TPB Disclosure Questionnaire (TPB-DQ) measuring attitudes and intentions to disclose the donor conception to the child, and disclosure behavior was assessed at both T4 and T5. Data from those participants who had not yet disclosed at T4 were analyzed using survival analysis with Cox regressions. MAIN RESULTS AND THE ROLE OF CHANCE: Forty participants had not disclosed the donor conception to their children at T4 and, out of these, 13 had still not disclosed at T5. We found a significant association between scores of the TPB factor Subjective norms at T4 and their subsequent disclosure behavior at T5 (HR = 2.019; 95% CI: 1.36-3.01). None of the other factors were significantly associated with disclosure behavior. LIMITATIONS, REASONS FOR CAUTION: The present study concerns heterosexual-couple parents with children conceived following treatment with gametes from open-identity donors, which limits the generalizability of our findings to other groups and contexts. Other limitations include the risk of systematic attrition due to the longitudinal study design and decreased statistical power due to few participants. WIDER IMPLICATIONS OF THE FINDINGS: Our findings highlight the importance of perceived subjective norms for parents' disclosure behavior and indicate that the co-parent's opinion about disclosure is of particular relevance in this regard. Counselors should focus on supporting prospective parents to initiate and maintain a healthy and open dialogue about concerns around building a family with donor conception. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Swedish Research Council. The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.

71Privacy on thin ice? Considering the California Court of Appeal decision in Johnson v. Superior Court.PubMed

J A Plosker
Jurimetrics. 2001 Fall;42(1):73-83.
In Johnson v. Superior Court, the California Court of Appeal determined that a provision of a contract limiting the discovery of the identity of a sperm donor was against public policy and that the privacy interest did not protect against disclosure of this information. Although the court's analysis of the public policy exception to the enforcement of contracts was unnecessary, the opinion properly balances California's and petitioners' interests against an anonymous donor's privacy right.

72Improvement in cystic fibrosis newborn screening program outcomes with genetic counseling via telemedicine.PubMed

Heather J Stalker, Amy R Jonasson, Sidney M Hopfer, et al.
Pediatr Pulmonol. 2023 Dec;58(12):3478-3486. doi: 10.1002/ppul.26678. Epub 2023 Sep 15.
INTRODUCTION: The Cystic Fibrosis Foundation (CF Foundation) recommends the provision of genetic counseling (GC) to help educate families and decrease anxiety around the cystic fibrosis (CF) newborn screening process. Unfortunately, access to genetic counselors is limited, especially for CF trained genetic counselors. We hypothesized that the GC process for families could be improved by utilizing telemedicine to leverage the availability of two dedicated, CF trained genetic counselors to provide access to GC for several CF centers. In addition, we hoped to demonstrate that use of trained CF genetic counselors, delivering GC via telemedicine at the time of sweat testing, would provide families with understanding of CF genetics as well as result in high satisfaction with the newborn screening process. METHODS: GC was provided by CF trained genetic counselors via telemedicine at the time of sweat testing. Following the counseling session, families were administered an anonymous written survey to evaluate their impression of the services provided. A subset of 50 families was recruited for an assessment of gained knowledge regarding CF genetics using the Ciske knowledge inventory. Using χ analysis, Ciske knowledge inventory data from our telemedicine GC families was compared to counseled and uncounseled Ciske historical controls. Lastly, in-depth interviews about the newborn screening process for CF were performed with 10 families and interviews were coded for emerging themes. RESULTS: During the 4 years of the study, 250 patients received GC. Overall comfort with the counseling rated 4.77 out of 5 using a Likert scale. After counseling by telemedicine, parents demonstrated improved understanding of the genetic implications of an abnormal CF newborn screen for their family, with 100% of families understanding that their child was a carrier for CF as compared to 97.2% of counseled (p = .023) and 78.5% of uncounseled (p = .0007) from Ciske historical controls. The study group also showed improvement in understanding of both parents possibly being carriers, with an 87.7% correct response rate compared to a 37.0% correct response rate in the counseled group (p < .0001) and a 35.4% correct response rate in the non-counseled group (p < .0001) from Ciske historical controls. Subgroup analysis at one site showed a significant increase in the number of infants with completed sweat tests from previous years (49% in 2013 vs. 80% in 2017 during the study, p < .0001). CONCLUSIONS: GC by telemedicine was well received by families and demonstrated improved family knowledge acquisition and understanding of CF as it related to risks for their child as well as identification of risks for other family members. Furthermore, in addition to an increase is those receiving GC, a subgroup analysis demonstrated a significant increase in the number of infants receiving sweat tests. This study demonstrates that GC via telemedicine for CF is feasible and demonstrates improvement in parent understanding of CF genetics. Furthermore, this method can be implemented effectively across a wide geographical area with a limited number of CF trained genetic counselors to improve access to care for patients and families.