The D631Y mutation of the rearranged during transfection (RET) gene might have higher tumorigenic potential than the C630Y mutation, but lower tumorigenic potential than the C634R/W mutation, a study published in the Korean Journal of Internal Medicine found.
These results can imply different clinical consequences for RET variants in medullary thyroid carcinoma (MTC).
The study enrolled 7 families (34 individuals) with the D631Y mutation, of which 4 had already been reported in the literature. The penetrance of MTC in carriers with D631Y was 32.3%, while in those with the C634R/W
mutation was 90%.
The age of onset of MTC was higher for those with D631Y mutations than C634R/W mutations (22 years vs < 3 years). The median age at diagnosis was also higher in patients with the RET D631Y variant when compared to those with the C634R/W variant.
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“It seems reasonable to consider deferring prophylactic thyroidectomy beyond the age of 5 in patients with the D631Y mutation,” Lee et al said about the observations. However, they advised that this seeks confirmation in additional studies.
Lee et al also constructed expression vectors that mimicked wild-type and mutant versions of RET to evaluate their effect on cell signaling. The results suggested that the RET mutation is involved in tumorigenesis by regulating cell proliferation, differentiation, and migration.
Cells expressing mutant RET (ie, D631Y, C630Y, or C634R/W) had increased phosphorylation levels of RET, AKT, and phosphoinositide 3-kinase. Moreover, the D631Y mutant inhibited the phosphorylation of glycogen synthase kinase-3 beta while increasing the expression levels of c-Myc, cyclin D1, and phosphorylated extracellular signal-regulated kinase.
Germline mutations in RET are known to cause multiple endocrine neoplasia type 2 (MEN2), a condition that leads to the development of tumors in 2 or more organs. MEN2 is associated with MTC, pheochromocytoma, and primary hyperparathyroidism.
Lee J, Kim SY, Jo KH, et al. Clinical features and signaling effects of RET D631Y variant multiple endocrine neoplasia type 2 (MEN2). Korean J Intern Med. Published online December 15, 2021. doi:10.3904/kjim.2021.311