Valkna Anu, Juchnewitsch Anna-Grete, Põlluaas Lisanna, Lillepea Kristiina, Tjagur Stanislav, Dutta Avirup, Pomm Kristjan, Punab Margus, Laan Maris
Chair of Human Genetics, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
Andrology Clinic, Tartu University Hospital, Tartu, Estonia.
Hum Reprod Open. 2025 Feb 21;2025(2):hoaf008. doi: 10.1093/hropen/hoaf008. eCollection 2025.
What is the load and profile of hereditary cancer-linked germline variants in infertile compared to fertile men?
This study showed almost 5-fold enrichment of disease-causing findings in hereditary cancer genes in infertile compared to fertile men (6.9% vs 1.5%, =2.3 × 10).
Epidemiological studies have revealed that men with low sperm count have a 2-fold higher risk of developing cancer during their lifetime. Our recent study observed a 4-fold increased prevalence of cancer in men with monogenic infertility compared to the general male population (8% vs 2%). Shared molecular etiologies of male infertility and cancer have been proposed.
This retrospective study analyzed germline likely pathogenic and pathogenic (LP/P) variants in 157 hereditary cancer genes in 522 infertile and 323 fertile men recruited to the ESTonian ANDrology (ESTAND) cohort.
PARTICIPANTS/MATERIALS SETTING METHODS: All study participants (n = 845) had been recruited and phenotyped at an Andrology Clinic. Identification of LP/P variants in the cancer gene panel was performed from an exome sequencing dataset generated for the study cohort. All variants passed an automated filtering process, final manual assessment of pathogenicity, and experimental confirmation using Sanger sequencing. Retrospective general health records were available for 36 out of 41 (88%) men with LP/P findings.
Infertile men presented a nearly 5-fold higher load of LP/P findings (36 of 522 cases, 6.9%) compared to fertile subjects (5 of 323, 1.5%; odds ratio (OR) = 4.7, 95% CI 1.81-15.5; = 2.3 × 10) spanning over 24 hereditary cancer genes. The prevalence of findings was not significantly different between azoospermic and oligozoospermic cases. There was also no enrichment of findings in men with a history of cryptorchidism. By the time of the study, six men carrying hereditary cancer variants had been diagnosed with a tumor. Family members affected with cancer had been documented for 10 of 14 cases with available pedigree health data.Nearly half of the infertile men with LP/P findings (17 out of 36) carried variants in genes belonging to the Fanconi anemia (FA) pathway involved in the maintenance of genomic integrity in mitosis and meiosis, repair of DNA double-stranded breaks, and interstrand crosslinks. Overall, FA-pathway genes (monoallelic) and (biallelic) were the most frequently affected loci (five subjects per gene).LP/P findings in pleiotropic genes linked to human development and hereditary cancer (, , , , , , ) were identified in several patients with syndromic phenotypes. Four cryptorchid infertile men were carriers of , , and variants implicated in Lynch syndrome. Future studies will reveal whether this observation is a by chance or replicable finding.Most hereditary cancer genes with LP/P variants show high expression in one or more testicular cell types, and mouse models for 15 of 24 affected genes have been reported to exhibit male sub- or infertility. These data support shared genetic etiology of impaired spermatogenesis and cancer. A significantly increased fraction of cancer-linked variants in infertile compared to fertile men could also explain the reported high prevalence of cancer as a comorbidity in male infertility.
All hereditary cancer-linked variants identified in this study have been submitted to the National Center for Biotechnology Information (NCBI) ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/).
All recruited participants were of white European ancestry and living in Estonia. Thus, the results might not apply to other ethnic groups. Due to the young age of study participants (median age 34.4 years), the true incidence of cancer during lifetime could not be assessed. As retrospective clinical data were not available for all men, it was not possible to evaluate all possible genotype-phenotype links. The absence of genetic data from family members precluded the assessment of the hereditary nature of the variants or their potential occurrence.
Infertility affects about 7-10% of men worldwide. In this study, one in 15 men with spermatogenic failure carried germline LP/P variants in hereditary cancer genes. As exome sequencing is gradually entering the molecular diagnostics setup in andrology, analyzing hereditary cancer-linked variants in the workup of infertile men will offer additional clinical benefits. Male factor infertility is typically diagnosed in men in their 30s, often before the onset of cancer or its symptoms. Early knowledge of germline predisposition to cancer enables timely screening and multidisciplinary management options, potentially improving the prognosis. The study data provide support for the shared monogenic etiologies of hereditary cancer and spermatogenic failure.
STUDY FUNDING/COMPETING INTERESTS: This study was funded by the Estonian Research Council grant PRG1021 (M.L. and M.P.). The authors declare no conflicts of interest.
与可育男性相比，不育男性中与遗传性癌症相关的种系变异的负荷和特征是什么？
这项研究表明，与可育男性相比，不育男性中遗传性癌症基因的致病发现几乎富集了5倍（6.9% 对1.5%，P = 2.3×10⁻⁶）。
流行病学研究表明，精子数量低的男性一生中患癌症的风险高出2倍。我们最近的研究观察到，与一般男性人群相比，单基因不育男性患癌症的患病率增加了4倍（8% 对2%）。有人提出了男性不育和癌症的共同分子病因。
研究设计、规模、持续时间：这项回顾性研究分析了爱沙尼亚男科学（ESTAND）队列中招募的522名不育男性和323名可育男性的157个遗传性癌症基因中的种系可能致病和致病（LP/P）变异。
参与者/材料、环境、方法：所有研究参与者（n = 845）均在男科学诊所招募并进行了表型分析。癌症基因panel中LP/P变异的鉴定是从为研究队列生成的外显子组测序数据集中进行的。所有变异均通过了自动过滤过程、致病性的最终人工评估以及使用桑格测序的实验确认。41名有LP/P发现的男性中有36名（88%）有回顾性的一般健康记录。
与可育受试者相比，不育男性的LP/P发现负荷几乎高出5倍（522例中的36例，6.9%），可育受试者为（323例中的5例，1.5%；优势比（OR）= 4.7，95% CI 1.81 - 15.5；P = 2.3×10⁻⁶），涉及24个遗传性癌症基因。无精子症和少精子症病例之间发现的患病率没有显著差异。有隐睾病史的男性中发现也没有富集。在研究时，6名携带遗传性癌症变异的男性被诊断出患有肿瘤。14例有可用家系健康数据的病例中有10例记录了受癌症影响的家庭成员。几乎一半有LP/P发现的不育男性（36例中的17例）在参与有丝分裂和减数分裂中基因组完整性维持、DNA双链断裂修复和链间交联的范可尼贫血（FA）途径的基因中携带变异。总体而言，FA途径基因（单等位基因）和（双等位基因）是最常受影响的位点（每个基因5名受试者）。在几名有综合征表型的患者中鉴定出了与人类发育和遗传性癌症相关的多效性基因（，，，，，，）中的LP/P发现。4名隐睾不育男性是与林奇综合征相关的，，和变异的携带者。未来的研究将揭示这一观察结果是偶然发现还是可重复的发现。大多数有LP/P变异的遗传性癌症基因在一种或多种睾丸细胞类型中显示高表达，并且据报道24个受影响基因中的15个的小鼠模型表现出雄性亚不育或不育。这些数据支持精子发生受损和癌症的共同遗传病因。与可育男性相比，不育男性中与癌症相关的变异比例显著增加也可以解释报告的男性不育中癌症作为合并症的高患病率。
本研究中鉴定的所有与遗传性癌症相关的变异已提交至美国国家生物技术信息中心（NCBI）的ClinVar数据库（https://www.ncbi.nlm.nih.gov/clinvar/）。
局限性、谨慎的原因：所有招募的参与者均为欧洲白人血统且居住在爱沙尼亚。因此，结果可能不适用于其他种族群体。由于研究参与者年龄较小（中位年龄34.4岁），无法评估一生中癌症的真实发病率。由于并非所有男性都有回顾性临床数据，因此无法评估所有可能的基因型 - 表型联系。缺乏家庭成员的遗传数据排除了对变异的遗传性或其潜在发生情况的评估。
不育影响全球约7 - 10%的男性。在本研究中，每15名精子发生失败的男性中有1名在遗传性癌症基因中携带种系LP/P变异。随着外显子组测序逐渐进入男科学的分子诊断设置，在不育男性的检查中分析与遗传性癌症相关的变异将带来额外的临床益处。男性因素不育通常在30多岁的男性中诊断，通常在癌症发病或出现症状之前。对癌症种系易感性的早期了解能够实现及时筛查和多学科管理选择，可能改善预后。研究数据为遗传性癌症和精子发生失败的共同单基因病因提供了支持。
研究资金/利益冲突：本研究由爱沙尼亚研究委员会PRG1021资助（M.L.和M.P.）。作者声明无利益冲突。
