Importance: RET pathogenic variants cause Multiple Endocrine Neoplasia type 2 (MEN2), characterised by medullary thyroid cancer (MTC). With increasing incidental identification of these variants in asymptomatic individuals outside family screening, their risk of MTC and all-cause mortality without intervention remain unknown in this context. Objective: To determine the risk of MTC and all-cause mortality in clinically unselected individuals and assess how the risk of MTC differ from clinically ascertained cases. Design, Setting, and Participants: Prospective cohort study of 383,914 unrelated individuals from the clinically unselected UK population (UK Biobank) and 122,640 from the US health system (Geisinger cohort). We compared MTC risk in these cohorts to 1,078 individuals who were clinically ascertained with suspicion of MEN2 from UK routine practice. Exposures: RET pathogenic variants causing MEN2 Main Outcomes and Measures: Frequency and the spectrum of pathogenic RET variants, Risk of clinically presented MTC, all-cause mortality without thyroidectomy. Results: Pathogenic RET variants were found in 0.04% of individuals from UK population cohort and 0.08% of individuals from US health system cohort. They were predominantly from moderate-risk category as per American Thyroid Association guideline (99.4% and 94.8% respectively). MTC risk by age 75 in variant carriers in the UK population was 2.2% (95% CI 0.7-6.8) and 19% (95% CI 5.7-30) in US health system cohort. This was significantly lower than the clinically ascertained cohort with the matched variants (95.7%, 95% CI 82.1-99.7 p<0.0001). In the UK Biobank, most variant carriers (98.2%) did not undergo thyroidectomy and their all-cause mortality by age 75 was similar to non-carriers (6.1%, 95% CI 2.7-13.8 vs 5.7%, 5.6-5.8, p=0.79), with consistent findings in the US health system cohort. Conclusions and Relevance: Moderate-risk RET variants are most common in incidental cases. These variants carry substantially lower MTC risk than clinically ascertained cases. This evidence addresses a current knowledge gap, enabling more informed clinical decision-making.
Competing Interest StatementThe authors have declared no competing interest.
Funding StatementThe current work is funded by the Wellcome Trust (219606/Z/19/Z) and summer studentship from Society of Endocrinology. The work is supported by the National Institute for Health Research (NIHR) Exeter Biomedical Research Centre, Exeter, UK.
Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
The UK Biobank Research Ethics Committee approved the study, and all participants provided written informed consent. Our study was reviewed by the Geisinger Institutional Review Board and determined not to be human subjects research as defined in 45CFR46.102(f) (Study #2016-0269).
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Yes
I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).
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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.
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Data AvailabilityAll data produced in the present study are available upon reasonable request to the authors.
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