RET codon 609 mutations: a contribution for better clinical managing

Abstract

Medullary thyroid carcinoma currently accounts for 5–8% of all thyroid cancers. The clinical course of this disease varies from extremely indolent tumors that can go unchanged for years to an extremely aggressive variant that is associated with a high mortality rate. As many as 75% of all medullary thyroid carcinomas are sporadic, with an average age at presentation reported as 60 years, and the remaining 25% are hereditary with an earlier age of presentation, ranging from 20 to 40 years.Germline RET proto-oncogene mutations are the genetic causes of multiple endocrine neoplasia type 2 and a strong genotype-phenotype correlation exists, particularly between a specific RET codon mutation and the (a) age-related onset and (b) thyroid tumor progression, from C-cell hyperplasia to medullary thyroid carcinoma and, ultimately, to nodal metastases. RET mutations predispose an individual to the development of medullary thyroid carcinomas and can also influence the individual response to RET protein receptor-targeted therapies.RET codon 609-point mutations are rare genetic events belonging to the intermediate risk category for the onset of medullary thyroid carcinoma. A large genealogy resulting in a less aggressive form of medullary thyroid carcinoma is associated with the high penetrance of pheochromocytoma and has been reported in the literature. In this short review article, we comment on our previous report of a large multiple endocrine neoplasia type 2A kindred with the same Cys609Ser germline RET mutation in which, conversely, the syndrome was characterized by a slightly aggressive, highly penetrant form of medullary thyroid carcinoma that was associated with low penetrance of pheochromocytoma and primary hyperparathyroidism.

Disease-modifying polymorphisms and C609Y mutation of RET associated with high penetrance of phaeochromocytoma and low rate of MTC in MEN2A

“…The RET proto-oncogene encodes for a transmembrane tyrosine kinase receptor and germline mutations are disease-causing in MEN2A (4), with different mutations having a strong genotype–phenotype correlation (3, 5). …”

“…It has been suggested that all individuals with MEN2A will develop MTC, with one-third developing phaeochromocytoma and one-third developing hyperparathyroidism (1). Although the penetrance of phaeochromocytoma and hyperparathyroidism is documented to be variable, there is general agreement that MTC is fully penetrant (3). Our kindred appear to have a less-aggressive thyroid phenotype and members of this family appear to have come to no harm by not having thyroidectomy at a young age.…”

“…There are further data to suggest that possession of two or more RET polymorphisms L769L, S836S, G691S and S904S in those with some RET disease-associated codon mutations can increase the likelihood of developing phaeochromocytoma, with presentation at a younger age (2), but there are no such data for those with mutations at codon 609. Moreover, there are conflicting data as to the penetrance of phaeochromocytoma in patients with codon 609 mutations (3), and it has even been questioned whether there is a need to screen for phaeochromocytoma in these patients (1). Here, our objective was to investigate an unusually high penetrance of phaeochromocytoma and low penetrance of MTC across three generations in a family with the C609Y mutation (Figure 1).…”

Unique association of multiple endocrine neoplasia 2A and congenital anomalies of the kidney and urinary tract in a child with a RET mutation

“…The main pathogenic variants within RET that cause MEN2A are located in codon 634 of exon 11 or codons 609, 611, 618 and 620 of exon 10. The most common pathogenic variant affects codon 634, accounting for 80% of MEN2A cases 11. Extra-endocrine manifestations, including 13% of patients with kidney anomalies were also found in patients with MEN2B caused by the classical MEN2B associated pathogenic RET variant p.M918T 12…”

A differential diagnosis of inherited endocrine tumors and their tumor counterparts

“…Recent data demonstrated that the two RET protein isoforms, namely RET9 and RET51, are important factors in the intracellular trafficking and maintenance of RET signaling (130). Interestingly, recent clinical approaches involving numerous RET mutation-positive MEN2 patients with specific exons or codon disturbances have been reported (61,131). These investigations provide new insights into mutation-specific risk profiles and have improved our understanding of genotype-phenotype correlations in MEN2 (114-116).…”