Additive effect of RET polymorphisms in MEN2A-associated hyperparathyroidism

Multiple Endocrine Neoplasia 2A (MEN2A) is characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism (HPT). RET polymorphisms have been associated with susceptibility and prognosis of MTC. Objective To evaluate the frequencies of RET polymorphisms (G691S, L769L, S836S e S904S) in MEN2A-patients and verify its association with susceptibility and age-dependent penetrance of HPT. Methods RET variants G691S, L769L, S836S, and S904S were evaluated in a cohort of 157 MEN2A patients. RET variant frequencies were compared between patients with and without HPT. Kaplan-Meier curves and Cox regression analysis estimated the effect of RET polymorphisms on the age-dependent penetrance. Results Sixteen percent of the patients presented MEN2A-associated HPT. The mean age at diagnosis was 35.3 ± 12.7 years; 71% were women. Female subjects had a higher risk of HPT (OR=2.61; 95%CI=1.04-6.55). Ninety percent of the patients had RET pathogenic variants at codon 634, and 60% had some RET polymorphisms. The frequencies of RET polymorphisms were similar between patients with or without HPT ( P =0.63). RET variant frequencies were as follows: 33.7% G691S/S904S, 33.1% L769L, 12.7% S836S, and no association was found between these frequencies and HPT development. Kaplan-Meier estimates of cumulative HPT diagnosis showed similar curves for patients harboring no, one polymorphism, and two or more polymorphisms ( P =0.066 ). Two or more RET variants compared to none or one polymorphism grouped, exhibited an increased risk for early HPT development ( P =0.015; OR 3.03; 95%CI 1.24-7.39). Conclusions RET polymorphism alleles have an additive effect on the estimated risk of age-related HPT development in MEN2A patients.