Population Prevalence of the Major Thyroid Cancer-Associated Syndromes.

Summary

Across All of Us and UK Biobank (>700,000 participants), MEN2 and PHTS are far more prevalent than previously thought, and many carriers (notably RET V804M/L) lack thyroid cancer diagnoses. These data support updating genetic testing and surveillance strategies, particularly for moderate-risk RET variants.

Key Findings

• MEN2 (RET), PHTS (PTEN), and FAP (APC) were significantly associated with thyroid cancer in logistic regression.
• Estimated prevalence: MEN2 ~1:2172 (All of Us) and 1:2348 (UK Biobank); PHTS ~1:8764 and 1:13043; FAP ~1:8461 and 1:8238.
• RET V804M/L variants comprised 65% of MEN2 variants in All of Us; none of these carriers had diagnosed thyroid cancer.

Clinical Implications

Consider broader germline testing and tailored surveillance for RET, PTEN, and APC variant carriers, with nuanced counseling for moderate-risk RET (e.g., V804M/L) given low penetrance for thyroid cancer.

Limitations

• Cross-sectional design with potential phenotype misclassification and incomplete clinical adjudication
• Reliance on ClinVar annotations; penetrance and expressivity not fully characterized

Future Directions

Prospective penetrance studies and guideline updates for genetic testing thresholds; evaluate outcomes of surveillance strategies in moderate-risk RET carriers.