RET Cys634Arg mutation confers a more aggressive multiple endocrine neoplasia type 2A phenotype than Cys634Tyr mutation

Abstract

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 7.6G6.9 years (1-32). Results: Patients (nZ173) 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, PZ0.007 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.

Phaeochromocytoma in multiple endocrine neoplasia type 2: RET codon‐specific penetrance and changes in management during the last four decades

“…Here we demonstrated that different amino acid substitutions in RET codon 634 were associated with significant differences in phaeo penetrance ( P <.0045, log‐rank test), with the highest penetrance in Cys634Arg substitution, followed by Cys634Tyr, Cys634Trp, Cys634Gly, and Cys634Phe (Figure ). These results are in agreement with findings from Japanese and Spanish studies. The Cys634Arg mutation is also associated with higher penetrance of MTC and primary hyperparathyroidism compared to other amino acid substitutions .…”

“…These results are in agreement with findings from Japanese and Spanish studies. The Cys634Arg mutation is also associated with higher penetrance of MTC and primary hyperparathyroidism compared to other amino acid substitutions . Different amino acid substitutions in codon 634 may alter the biochemistry of the RET receptor in the extracellular location, potentially inducing a variable degree of ligand‐independent protein dimerization.…”

Variability in penetrance of multiple endocrine neoplasia 2A with amino acid substitutions in RET codon 634

“…8 A recent Spanish Online National Database study linked substitution by arginine in cysteine codon 634 to higher penetrance of MTC, phaeochromocytoma and hyperparathyroidism than substitution by tyrosine. 9 In other series, substitution of cysteine with or without arginine had no effect on the age of thyroidectomy, 10,11 but was associated more often with metastatic involvement. 11 In previous publications, correction for multiple testing, if performed at all, was not employed consistently so that some of the findings presented actually may have been spurious (falsepositive).…”

“…The latter finding of greater penetrance of primary hyperparathyroidism among C634R carriers ( vs all other codon 634 carriers) was confirmed by another research group . A recent Spanish Online National Database study linked substitution by arginine in cysteine codon 634 to higher penetrance of MTC, phaeochromocytoma and hyperparathyroidism than substitution by tyrosine . In other series, substitution of cysteine with or without arginine had no effect on the age of thyroidectomy, but was associated more often with metastatic involvement …”

Nodular Thyroid Disease and Thyroid Cancer in the Era of Precision Medicine

“…Often, tumours show mutational heterogeneity, that is, RET mutations may be found in subpopulations of tumour cells rather than the entire tumour [70,71] . Different amino acid substitutions at a particular RET codon may be associated with phenotypes with different tumour aggressiveness [72] . An important limitation of genomic analysis is epigenetic influences.…”