West Courtney E, Mirshahi Uyenlinh L, Ruth Katherine S, Sharp Luke N, Arni Ankit M, Turnbull Clare, Wright Caroline F, Vaidya Bijay, Owens Martina M, Carey David J, Patel Kashyap A
Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, United Kingdom.
Department of Genomic Health, Geisinger, Danville, Pennsylvania.
JAMA Netw Open. 2025 Jun 2;8(6):e2517937. doi: 10.1001/jamanetworkopen.2025.17937.
RET germline pathogenic variants cause multiple endocrine neoplasia type 2 (MEN2), which is associated with medullary thyroid cancer. With increasing incidental identification of these variants in asymptomatic individuals outside family screening, these individuals' risk of medullary thyroid cancer and all-cause mortality without intervention remain unknown in this context.
To evaluate the risk of medullary thyroid cancer and all-cause mortality in clinically unselected individuals with incidentally identified RET variants and assess whether the risk of medullary thyroid cancer differs from those with clinically ascertained RET variants.
DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study of 383 914 unrelated individuals from the clinically unselected UK population (UK Biobank, recruited in 2006-2010, with follow-up to June 2023) and 122 640 unrelated individuals from a US health system (Geisinger MyCode cohort, recruited 2004-2020, with follow-up to October 2023) compared medullary thyroid cancer risk in these cohorts with 1078 individuals who were clinically ascertained with suspicion of MEN2 from a UK routine practice.
RET germline pathogenic variants causing MEN2.
Frequency and the spectrum of pathogenic RET variants, risk of clinically present medullary thyroid cancer, and all-cause mortality without thyroidectomy were assessed using proportions with exact binomial 95% CIs and survival analysis adjusted for age at recruitment and sex.
In the UK Biobank, 169 unrelated individuals (mean [SD] age at recruitment, 57.0 [8.1] years; 94 male [55.6%]) had a pathogenic RET variant (prevalence, 0.04% [95% CI, 0.04%-0.05%]). In the US health system-based cohort, 77 unrelated individuals (mean [SD] age at recruitment, 56.2 [17.8] years; 45 female [58.4%]) had a pathogenic RET variant (prevalence, 0.06% [95% CI, 0.05%-0.78%]). The variants were predominantly from the moderate-risk category per American Thyroid Association guidelines (168 individuals [99.4%] and 75 individuals [94.8%], respectively). The Kaplan-Meier estimated medullary thyroid cancer risk by age 75 years in variant carriers in the UK population was 2.2% (95% CI, 0.7%-6.9) and 19.3% (95% CI, 6.4%-30.2%) in US health system cohort. These risks were significantly lower compared with the clinically ascertained cohort with the matched variants (95.7% [95% CI, 82.1%-99.7%]). In the UK Biobank, most variant carriers (166 [98.2%]) did not undergo thyroidectomy, and their all-cause mortality by age 75 years was similar to noncarriers (6.1% [95% CI, 2.7%-13.8%] vs 5.7% [95% CI, 5.6%-5.8%]), with consistent findings in the US health system cohort.
In this cohort study, moderate-risk RET variants were most common in incidental cases. The variants were associated with a substantially lower medullary thyroid cancer risk than clinically ascertained cases. This evidence addresses a current knowledge gap, enabling more informed clinical decision-making.
RET基因种系致病性变异可导致2型多发性内分泌肿瘤（MEN2），这与甲状腺髓样癌相关。随着在家族筛查之外的无症状个体中偶然发现这些变异的情况越来越多，在这种情况下，这些个体未经干预时患甲状腺髓样癌的风险和全因死亡率仍不明确。
评估偶然发现RET变异的未经过临床选择的个体患甲状腺髓样癌的风险和全因死亡率，并评估甲状腺髓样癌的风险与临床确诊RET变异的个体是否不同。
设计、背景和参与者：这项前瞻性队列研究纳入了来自英国未经过临床选择的人群（英国生物银行，于2006 - 2010年招募，随访至2023年6月）的383914名无亲属关系的个体，以及来自美国医疗系统（盖辛格MyCode队列，于2004 - 2020年招募，随访至2023年10月）的122640名无亲属关系的个体，将这些队列中甲状腺髓样癌的风险与1078名因怀疑患有MEN2而经临床确诊的来自英国常规医疗的个体进行比较。
导致MEN2的RET基因种系致病性变异。
使用精确二项式95%置信区间的比例以及根据招募时年龄和性别进行调整的生存分析，评估致病性RET变异的频率和谱、临床出现甲状腺髓样癌的风险以及未进行甲状腺切除术时的全因死亡率。
在英国生物银行中，169名无亲属关系的个体（招募时的平均[标准差]年龄为57.0[8.1]岁；94名男性[55.6%]）携带致病性RET变异（患病率为0.04%[95%置信区间，0.04% - 0.05%]）。在美国基于医疗系统的队列中，77名无亲属关系的个体（招募时的平均[标准差]年龄为56.2[17.8]岁；45名女性[58.4%]）携带致病性RET变异（患病率为0.06%[95%置信区间, 0.05% - 0.78%]）。根据美国甲状腺协会指南，这些变异主要来自中度风险类别（分别为168名个体[99.4%]和75名个体[94.8%]）。英国人群中变异携带者到75岁时，根据Kaplan - Meier估计的甲状腺髓样癌风险为2.2%（95%置信区间，0.7% - 6.9%）；在美国医疗系统队列中为19.3%（95%置信区间，6.4% - 30.2%）。与临床确诊的具有匹配变异的队列相比，这些风险显著更低（95.7%[95%置信区间，82.1% - 99.7%]）。在英国生物银行中，大多数变异携带者（166名[98.2%]）未接受甲状腺切除术，他们到75岁时的全因死亡率与非携带者相似（6.1%[95%置信区间，2.7% - 13.8%]对5.7%[95%置信区间，5.6% - 5.8%]），在美国医疗系统队列中也有一致的发现。
在这项队列研究中，中度风险的RET变异在偶然发现的病例中最为常见。这些变异与甲状腺髓样癌风险显著低于临床确诊病例相关。这一证据填补了当前的知识空白，有助于做出更明智的临床决策。
