Prevalence of the major thyroid cancer-associated syndromes in the United States

Importance A subset of thyroid cancers develops in a setting of a known hereditary cancerassociated syndrome. Understanding the population prevalence of thyroid cancer-associated syndromes is important to guide germline genetic testing and clinical management.

To estimate the prevalence of the major thyroid cancer-associated syndromes in the United States using the All of Us Research Program (AoU) data. Design In this cohort study, we identified pathogenic and likely pathogenic (P/LP) variants from the ClinVar database in 245,394 AoU biobank participants. We performed a logistic regression analysis of the association of ClinVar P/LP variants with thyroid cancer. P/LP variants in the genes of interest were manually curated to ensure match and pathogenicity status. We calculated the prevalence of thyroid cancer-associated syndromes defined by the presence of P/LP variants.

Using logistic regression, we found that three hereditary syndromes, multiple endocrine neoplasia type 2 (MEN2, RET gene, p = 3.23e-20), PTEN hamartoma syndrome (PHPS, PTEN gene, p = 2.59e-15), and familial adenomatous polyposis type 1 (FAP, APC gene, p = 2.73e-10) were significantly associated with thyroid cancer. All these syndromes were previously reported to increase the risk of thyroid cancer. The prevalence of thyroid cancer-associated syndromes in the AoU was 1:2,172 (113 cases), 1:8,764 (28 cases), and 1:8,461 (29 cases) for MEN2, PHPS, and FAP, respectively. Most carriers of P/LP variants were not diagnosed with the features of the syndromes, including thyroid cancer, pheochromocytoma, or primary hyperparathyroidism. Three pathogenic RET variants that cause two amino acid substitutions, V804M and V804L, constitute 65% of all MEN2 variants in the AoU, and none of these carriers were diagnosed with thyroid cancer.

and Relevance The prevalence of MEN2 and PHPS is ∼10-20 times higher than it is currently estimated for the general population (1:35,000 – 1,50,000 for MEN2 and 1:200,000-1:250,000 for PHTS). Most affected individuals are not diagnosed with thyroid cancer. These results further refine our understanding of the prevalence of hereditary syndromic thyroid cancers and may change the clinical approach to patients with moderate-risk RET mutations (such as V804M and V804L), potentially emphasizing active surveillance over prophylactic thyroidectomy. Question What is the prevalence of the major thyroid cancer-associated syndromes in the United States? Findings In this cohort study that includes 245,394 genotyped participants in the All of Us Research Program (AoU), the prevalence was 1:2,172 for multiple endocrine neoplasia type 2 (MEN2) and 1:8,764 for PTEN hamartoma syndrome (PHTS). Meaning The prevalence of MEN2 and PHPS is ∼10-20 times higher than currently estimated for the general population. Competing Interest Statement The authors have declared no competing interest. Clinical Protocols https://github.com/pozdeyevlab/clinvar-tc Funding Statement This study was funded by National Cancer Institute R21 1R21CA282380 to Nikita Pozdeyev and Christopher Gignoux, and the Colorado Clinical and Translational Sciences Institute grant CO-J-24-170 to Nikita Pozdeyev. Author Declarations I 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: De-identified clinical and genetic data was provided by the All of Us Research program (https://allofus.nih.gov/). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. 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). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data produced in the present work are contained in the manuscript