Additive effect of RET polymorphisms in MEN2A-associated hyperparathyroidism

Abstract Introduction 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, and S904S) in MEN2A patients and verify their 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 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 polymorphism, 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. Significance statement Germline pathogenic variants in the RET proto-oncogene are a well-known genetic cause of multiple endocrine neoplasia type 2A (MEN2A). This rare hereditary cancer syndrome predisposes individuals to the development of MTC, pheochromocytoma, and primary hyperparathyroidism (HPT). This study investigated the association between RET polymorphisms and MEN2A-associated HPT, a common and often asymptomatic manifestation of the disease. Our findings suggest that cumulative RET polymorphisms may be associated with an increased risk of HPT in MEN2A patients, and this risk may be influenced by age and gender. These findings may contribute to the refinement of risk stratification and the personalization of surveillance protocols in individuals carrying RET pathogenic variants.