unveiling a Hidden Epidemic: Thyroid Cancer Syndromes Far More Prevalent Than Previously Believed
New research published in the Journal of Clinical Endocrinology and Metabolism suggests that the prevalence of Multiple Endocrine neoplasia type 2 (MEN2) and PTEN Hamartoma Syndrome (PHTS) might potentially be significantly underestimated, possibly affecting 10 to 20 times more individuals than current estimates indicate. This groundbreaking study, drawing data from the All of Us Research Program (AoU) and the UK Biobank, highlights a critical gap in clinical practice: the underutilization of genetic assessments for thyroid cancer susceptibility, despite the substantial role genetic variants play.
The inquiry focused on identifying pathogenic or likely pathogenic (P/LP) variants associated with thyroid cancer. In the AoU cohort, which included 2097 patients with a history of thyroid cancer and available genotype data, researchers identified 113 carriers of P/LP variants in the RET proto-oncogene.This translates to a MEN2 prevalence of approximately 1:2172, and even higher at 1:2697 when a more restrictive definition was applied.The UK Biobank data corroborated these findings, with 200 RET carriers indicating a MEN2 prevalence of 1:2348. Notably,all identified RET P/LP variant carriers were heterozygous,and a significant portion of these individuals did not present with overt MEN2 symptoms,suggesting a large undiagnosed population. For those with RET P/LP variants and a thyroid cancer diagnosis,the average age of diagnosis was 55.8 years.
The study also shed light on PHTS, revealing 28 individuals in AoU carrying PTEN P/LP variants, resulting in a prevalence of 1:8764. The UK Biobank data showed 36 PTEN P/LP variant carriers, with a prevalence of 1:13,043. Similar to MEN2, all PTEN P/LP variant carriers were heterozygous.While few individuals with PTEN P/LP variants in AoU were diagnosed with thyroid cancer, those who were had a mean age of diagnosis of 28 years.Furthermore, the research identified variants in the APC regulator of WNT signaling pathway (APC) in 29 individuals from AoU (prevalence, 1:8461) and 57 from the UK Biobank (prevalence, 1:8238).These carriers were also heterozygous, with 20 or fewer diagnosed with thyroid cancer, and a mean age of diagnosis of 37 years.A key limitation acknowledged by the study authors is the exclusion of data pertaining to the genetic contribution to nonmedullary thyroid cancer.
The study’s authors conclude with a crucial implication for clinical management: “We found that most of these individuals have not been diagnosed with thyroid cancer. Likely, active surveillance with neck ultrasound and serum calcitonin for most carriers of moderate-risk mutations in RET is appropriate, and the risk of overtreatment is high.” This suggests a need for a paradigm shift in how individuals with these genetic predispositions are managed, emphasizing proactive monitoring over immediate aggressive intervention for many.
This research, originally featured on Endocrinology Advisor, underscores the urgent need to integrate genetic screening into routine clinical care for thyroid cancer risk assessment, potentially identifying and managing a far larger segment of the population than previously understood.
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Disclosure: Several authors of the study have declared affiliations with biotech, pharmaceutical, and/or device companies. For a thorough list of author disclosures, please refer to the original publication.*
