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. 2025 Jun 2;8(6):e2517937.
doi: 10.1001/jamanetworkopen.2025.17937.

Medullary Thyroid Cancer Risk and Mortality in Carriers of Incidentally Identified MEN2A RET Variants

Courtney E West  1 , Uyenlinh L Mirshahi  2 , Katherine S Ruth  1 , Luke N Sharp  1 , Ankit M Arni  1 , Clare Turnbull  3 , Caroline F Wright  1 , Bijay Vaidya  1   4 , Martina M Owens  5 , David J Carey  2 , Kashyap A Patel  1
Affiliations

Medullary Thyroid Cancer Risk and Mortality in Carriers of Incidentally Identified MEN2A RET Variants

Courtney E West et al. JAMA Netw Open. .

Erratum in

  • Error in Figure 1.
    [No authors listed] [No authors listed] JAMA Netw Open. 2025 Aug 1;8(8):e2528458. doi: 10.1001/jamanetworkopen.2025.28458. JAMA Netw Open. 2025. PMID: 40748643 Free PMC article. No abstract available.

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.

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.

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.

Exposures: RET germline pathogenic variants causing MEN2.

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.

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.

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Ruth reported receiving salary support from UK Research and Innovation during the conduct of the study. Prof Wright reported receiving grants from the Medical Research Council during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. The Age-Related Risk of Medullary Thyroid Cancer in Individuals With Pathogenic RET Variants in a Clinically Unselected UK Biobank Cohort
A. Any thyroidectomy included partial, total, or subtotal for any indication by RET pathogenic variant status (n = 169 carriers and 383 745 noncarriers). The error bars represent 95% CIs. B and C. Log-rank tests showed significant differences between RET carriers and noncarriers (P < .001 for medullary thyroid cancer; P = .02 for broad definition).
Figure 2.
Figure 2.. Risk of Medullary Thyroid Cancer in Clinically Unselected Individuals With Pathogenic RET Variants Replicated in Health System–Based Cohort
A. Any thyroidectomy included partial, total, or subtotal for any indication by RET pathogenic variant status (n = 77 carriers and 122 563 noncarriers). The error bars represent 95% CIs. B and C. Log-rank test showed significant differences between RET carriers and noncarriers (P < .001 for medullary thyroid cancer and for broad definition).
Figure 3.
Figure 3.. Pathogenic RET Variant Carrier and Noncarrier All-Cause Mortality Without Prophylactic Thyroidectomy
Figure 4.
Figure 4.. Age-Related Risk of Medullary Thyroid Cancer in Individuals With RET Pathogenic Variant Ascertained Clinically and in a Clinically Unselected Population and Health System–Based Cohort With the Matched Variants
See this image and copyright information in PMC

References

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