Endocrine Abstracts

Background: MEN2A-causing RET variants are considered highly penetrant, and early prophylactic thyroidectomy is recommended to prevent the development of Medullary thyroid cancer (MTC). However, existing risk estimates may be exaggerated due to their reliance on clinically selected patients, leading to unnecessary surgeries. To address this, we conducted a comprehensive study of 450,000 clinically unselected individuals to evaluate the risk of MTC with pathogenic RET variants.

Methods: We analysed whole exome sequencing and deep phenotype data on 450,000 people from clinically unselected UK biobank cohort. We defined variant pathogenic if it is previously reported in MEN2A cases and fulfilled the American college of medical genetics criteria. To identify MTC cases, we utilised self-reported, cancer registry, general practice, and hospital records data. We use two definitions of MTC: definitive (medullary histology) and potential (thyroid cancer, thyroid surgery or thyroid replacement).

Results: Our analysis identified 193 carriers (age range 56-86) with 18 distinct pathogenic RET variants. Of these, 7 were high/moderate-risk variants according to the American Thyroid Association (ATA) guideline, and 11 were low risk variants. The risk of definitive MTC was found to be extremely low at 1.6% (3/193, 95% CI 0.3-4.5). The risk remained similarly low at 6.7% (13/193, 95% CI 3.6–11.2) for much broader potential MTC definition. The penetrance of potential MTC for carriers with high/moderate risk variants was slightly higher but still low at 16.0% (4/25 95% CI 4.5-36.1). V894M variant was the most common with 111 carriers and had very low risk of definitive MTC (0.95%).

Conclusion: This largest study to date involving clinically unselected individuals, challenges the current understanding of MTC penetrance associated with MEN2A-causing RET mutations. Our findings strongly advocate for a reconsideration of the prevailing approach of early prophylactic thyroidectomy when these pathogenic variants are incidentally detected before the onset of MTC.