Objective: Specific germline mutations in the RET proto-oncogene are correlated with clinical features in multiple endocrine neoplasia type 2A (MEN2A); however, data are scarce regarding differences in clinical profiles dependent on the type of nucleotide and amino acid substitution at the same codon. We aimed to analyse differences in clinical risk profiles and outcomes among different amino acids encoded by codon 634.
Design: The study was retrospective and multicentric.
Methods: We collected data included in the Spanish Online National Database from patients with MEN2A carrying a RET proto-oncogene mutation on codon 634. The mean follow-up time was 7.6±6.9 years (1-32).
Results: Patients (n=173) from 49 unrelated families were C634Y carriers, and 26 patients from eight different families had C634R mutation. We found higher penetrance of medullary thyroid carcinoma, phaeochromocytoma and hyperparathyroidism (P<0.001, P=0.007 and P<0.001 respectively) in C634R carriers than in C634Y carriers. The Kaplan-Meier estimate of cumulative lymph node and distant metastases rates showed that these events occurred earlier in patients harbouring the C634R mutation (P<0.001). A multivariate adjusted Cox regression analysis indicated that the C634R mutation was an independent factor for persistent/recurrent disease (hazard ratio, 3.17; 95% CI: 1.66-6.03; P<0.001).
Conclusions: Our results suggest that there could be clinical differences caused by different amino acid substitutions at codon 634; specifically, the C634R mutation was associated with a more aggressive MEN2A phenotype than the C634Y mutation.
© 2015 European Society of Endocrinology.