Hypothesizing a role of ret hyperactivation on weight control in patients with type 2A multiple endocrine neoplasia (MEN2A)

Introduction: RET gene is responsible for various human cancers and is mutated and hyperactivated in nearly 100% of familial (germline mutation) and in about 60% of sporadic (somatic mutation) MTC cases. Moreover, RET gene play a role in several physiologic and pathologic conditions. Very recently, the hyperfunction of RET was found to be a key process in weight loss. The hypothesis is that in a peculiar population in which RET gene is mutated and constitutively activated from birth, RET hyperfunction could be a factor in weight loss. Objectives: To evaluate potential differences in weight at the diagnosis in RET germline positive (gRET+) vs RET germline negative (gRET-) MTC cases. Methods: 98 gRET+ MTC patients, all index cases of different families, were matched one-to-one according to gender and age at diagnosis, with 98 gRET-. Anthropometric data were collected for all patients. Results: Each group had 39 males and 59 females. Median age at diagnosis was 47 years old in both groups. In all population median weight was 69 Kg (IQR 60-80) and BMI 24.7 Kg/m^2 (IQR 22.1-27.7). Therefore, 2.0% of patients were underweight (BMI ≤ 18.4), 51.6% normal weight (18.5-24.9), 30.6% overweight (25-29.9) and 15.8% obese (≥ 30). No difference in obesity prevalence was observed in patients with or without RET germline mutations (17.3% vs 14.3%, p>0.05), as well as in BMI and weight (p>0.05 for both). Moreover, analysing the distribution of BMI according to the different types of RET mutation, again no difference was observed. When dividing patients according to gender, in females, we confirmed that BMI and weight did not differ between gRET+ and gRET-. Conversely, in males, gRET+ patients showed higher BMI values (median 26.9 vs 24.6), more frequently > 30 (30.7% vs 12.3%) and weight (median 83 vs 77 Kg) than gRET- (P < 0.05 for all). Conclusions: No differences in weight and BMI were highlighted in our matched cohort population of gRET+ and gRET- patients. Differently from the initial hypothesis and animal models, although only in males, gRET+ patients showed higher weight and BMI than gRET-. Further studies with larger number of patients are needed to unveil the potential effect of RET hyperactivation on human weight control.