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