Abstract
Gain-of-function germline mutations of the RET proto-oncogene are responsible for initiation of carcinogenesis within the thyroid gland and development of hereditary form of medullary thyroid carcinoma and MEN2 syndrome. Genotype-phenotype correlations are established for most RET mutations, but the importance of the synonymous changes in this gene remains debatable. We aimed to analyze RET gene variants in Polish population. Genetic testing for the RET gene variants was performed with standard methods in 585 people aged 1–85, including 448 patients with medullary thyroid carcinoma and 131 of their first- and second-degree relatives, as well as six patients suspected of MTC/MEN2. Besides the most frequent synonymous changes, p.Leu769Leu, p.Ser836Ser, and p.Ser904Ser, four rare changes—c.1827C>T (p.Cys609Cys), c.2364C>T (p.Ile788Ile), c.2418C>T (p.Tyr806Tyr), and c.2673G>A (p.Ser891Ser)—were found in the RET gene, in the Polish population. Two of the rare changes, p.Cys609Cys and p.Ile788Ile, had not been previously described. The frequency of molecular synonymous variants in the general population was evaluated by testing 400 anonymous blood samples of neonates. Our findings may contribute to a better understanding of the genetic diversity of the RET gene and the involvement of synonymous variants in this diversity.
Highlights
Proto-oncogene RET encodes a single-pass transmembrane receptor of the tyrosine kinase family
Germline gain-of-function mutations in the RET proto-oncogene are associated with type 2 multiple endocrine neoplasia syndromes (MEN2A or MEN2B) and familial medullary thyroid carcinoma (FMTC) [4,5,6,7]
Three hundred seventy patients (81.5% of patient group) were diagnosed with sporadic Medullary thyroid carcinoma (MTC) and five patients suspected of MTC/MEN2 with other diseases (1.1% of patient group) (Table 1)
Summary
Proto-oncogene RET (rearranged during transfection) encodes a single-pass transmembrane receptor of the tyrosine kinase family. Germline gain-of-function mutations in the RET proto-oncogene are associated with type 2 multiple endocrine neoplasia syndromes (MEN2A or MEN2B) and familial medullary thyroid carcinoma (FMTC) [4,5,6,7]. Considering MTC aggressiveness and the co-existing endocrinopathies such as pheochromocytoma (PHEO), hyperparathyroidoism (HPTH), cutaneous lichen amyloidosis (CLA), and Hirschsprung’s disease (HD), the American Thyroid Association (ATA) Guidelines currently divide germline RET mutations into three risk categories: ATA– HST (the highest risk—patients with MEN2B and the RET codon M918T mutation), ATA-H (the high risk—patients with RET codon C634 mutations and the RET codon A883F mutation), and ATA-MOD (moderate risk—patients with all other mutations in the RET gene) [9]
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