| Title: | Medullary Thyroid Cancer Risk and Mortality in Carriers of Incidentally Identified MEN2A RET Variants |
| Journal: | JAMA Network Open |
| Published: | 2 Jun 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40577012/ |
| DOI: | https://doi.org/10.1001/jamanetworkopen.2025.17937 |
Publication 16260
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Abstract
Importance: 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.</p>
Objective: 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.</p>
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.</p>
Exposures: RET germline pathogenic variants causing MEN2.</p>
Main Outcomes and Measures: 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.</p>
Results: 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.</p>
Conclusions and Relevance: 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.</p>
16 Keywords
- Adult
- Aged
- Carcinoma, Neuroendocrine
- Female
- Genetic Predisposition to Disease
- Germ-Line Mutation
- Heterozygote
- Humans
- Incidental Findings
- Male
- Middle Aged
- Multiple Endocrine Neoplasia Type 2a
- Prospective Studies
- Proto-Oncogene Proteins c-ret
- Thyroid Neoplasms
- United Kingdom
11 Authors
- Courtney E. West
- Uyenlinh L. Mirshahi
- Katherine S. Ruth
- Luke N. Sharp
- Ankit M. Arni
- Clare Turnbull
- Caroline F. Wright
- Bijay Vaidya
- Martina M. Owens
- David J. Carey
- Kashyap A. Patel
1 Application
| Application ID | Title |
|---|---|
| 103356 | Understanding the role of rare and common genetic variation in human phenotypes |
Enabling scientific discoveries that improve human health