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

Objective Controversy surrounds the importance of the different amino acids substituting for cysteine in REarranged during Transfection (RET) codon 634 for multiple endocrine neoplasia 2A (MEN 2A). This study aimed to clarify the relevance of these amino acid substitutions for the development of MEN 2A. Design Cross-sectional study at surgical referral centres in Germany. Patients Included were 184 carriers of RET mutations in codon 634. Measurements Arginine (79 carriers) and tyrosine (50 carriers) substitutions in codon 634 were compared with each other and, for the first time, gauged against a common reference standard comprising all other amino acid substitutions (phenylalanine, 35 carriers; serine, 12 carriers; glycine, 7 carriers; tryptophan, 1 carrier). Results Arginine substitutions in codon 634 were associated with higher penetrance of medullary thyroid cancer (MTC; 82% vs 62%; P = 0.010), any phaeochromocytoma (44% vs 15%, P < 0.001), bilateral phaeochromocytoma (32% vs 5%; P < 0.001) and primary hyperparathyroidism (18% vs 5%; P = 0.039) relative to the reference standard. The penetrance rates of any phaeochromocytoma (44% vs 26%; P = 0.041) and bilateral phaeochromocytoma (32% vs 14%; P = 0.035) were also higher with arginine than with tyrosine substitutions. Corrected for multiple testing, the associations of arginine with any phaeochromocytoma and bilateral phaeochromocytoma remained statistically significant. Progression of MTC, evidenced by largest primary tumour diameter, nodal status, distant metastasis and biochemical cure, did not differ by amino acid substitution. Conclusions In codon 634, arginine substitutions for cysteine may cause slightly higher penetrance rates of MEN 2A which, overall, are too small to treat carriers differently. The mode of action by which arginine exerts these subtle effects warrants further research.