{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T05:45:30Z","timestamp":1792043130305,"version":"4.4.0"},"reference-count":33,"publisher":"American Medical Association (AMA)","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"\n Importance<\/jats:title>\n \n RET<\/jats:italic>\n 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\u2019 risk of medullary thyroid cancer and all-cause mortality without intervention remain unknown in this context.\n <\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n \n To evaluate the risk of medullary thyroid cancer and all-cause mortality in clinically unselected individuals with incidentally identified\n RET<\/jats:italic>\n variants and assess whether the risk of medullary thyroid cancer differs from those with clinically ascertained\n RET<\/jats:italic>\n variants.\n <\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n This prospective cohort study of 383\u202f914 unrelated individuals from the clinically unselected UK population (UK Biobank, recruited in 2006-2010, with follow-up to June 2023) and 122\u202f640 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.<\/jats:p>\n <\/jats:sec>\n \n Exposures<\/jats:title>\n \n RET<\/jats:italic>\n germline pathogenic variants causing MEN2.\n <\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n \n Frequency and the spectrum of pathogenic\n RET<\/jats:italic>\n 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.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n In the UK Biobank, 169 unrelated individuals (mean [SD] age at recruitment, 57.0 [8.1] years; 94 male [55.6%]) had a pathogenic\n RET<\/jats:italic>\n variant (prevalence, 0.04% [95% CI, 0.04%-0.05%]). In the US health system\u2013based cohort, 77 unrelated individuals (mean [SD] age at recruitment, 56.2 [17.8] years; 45 female [58.4%]) had a pathogenic\n RET<\/jats:italic>\n 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.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n \n In this cohort study, moderate-risk\n RET<\/jats:italic>\n 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.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2025.17937","type":"journal-article","created":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T11:30:35Z","timestamp":1751023835000},"page":"e2517937","source":"Crossref","is-referenced-by-count":15,"title":["Medullary Thyroid Cancer Risk and Mortality in Carriers of Incidentally Identified MEN2A\n RET<\/i>\n Variants"],"prefix":"10.1001","volume":"8","author":[{"given":"Courtney E.","family":"West","sequence":"first","affiliation":[{"name":"Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uyenlinh L.","family":"Mirshahi","sequence":"additional","affiliation":[{"name":"Department of Genomic Health, Geisinger, Danville, 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