Abstract
Background: Pathogenic germline mutations affecting the RET proto-oncogene underlie the development of hereditary medullary thyroid carcinoma (MTC). The aims of this study were to evaluate the prevalence of germline RET mutations in a large series of MTC, collected over the last 25 years, and to reappraise their clinical significance. Methods: We performed RET genetic screening in 2031 Italian subjects: patients who presented with sporadic (n = 1264) or hereditary (n = 117) MTC, plus 650 relatives. Results: A RET germline mutation was found in 115/117 (98.3%) hereditary and in 78/1264 (6.2%) apparently sporadic cases: in total, 42 distinct germline variants were found. The V804M mutation was the most prevalent in our cohort, especially in cases that presented as sporadic, while mutations affecting cysteine residues were the most frequent in the group of clinically hereditary cases. All M918T mutations were “de novo” and exclusively associated with MEN2B. Several variants of unknown significance (VUS) were also found. Conclusions: a) RET genetic screening is informative in both hereditary and sporadic MTC; b) the prevalence of different mutations varies with V804M being the most frequent; c) the association genotype–phenotype is confirmed; d) by RET screening, some VUS can be found but their pathogenic role must be demonstrated before screening the family.
Highlights
Medullary Thyroid Carcinoma (MTC) can be either sporadic or hereditary
In addition to the classical cysteine mutations, which were originally shown to be associated with the multiple endocrine neoplasia type 2A (MEN2A) [4] and the M918T mutation that is causative of MEN2B [8], over the years additional RET mutations have been discovered mainly in familial MTC (FMTC)
Germline RET mutation was found in 78/1264 (6.2%) MTC patients who were diagnosed as sporadic according to their negative familial history and absence of other endocrine neoplasms
Summary
Medullary Thyroid Carcinoma (MTC) can be either sporadic or hereditary. The hereditary form gives origin to the Multiple Endocrine Neoplasia (MEN) disorders in which thyroid carcinoma can be associated with additional endocrine neoplasia such as pheochromocytoma and/or hyperparathyroidism (MEN2A) and with non endocrine diseases such as mucosal neuromas, megacolon, marfanoid habitus and skeletal abnormalities (MEN2B). In addition to the classical cysteine mutations, which were originally shown to be associated with the multiple endocrine neoplasia type 2A (MEN2A) [4] and the M918T mutation that is causative of MEN2B [8], over the years additional RET mutations have been discovered mainly in FMTC These mutations occur mostly in cysteines, but can affect non-cysteine codons, mainly at. Pathogenic germline mutations affecting the RET proto-oncogene underlie the development of hereditary medullary thyroid carcinoma (MTC). Conclusions: a) RET genetic screening is informative in both hereditary and sporadic MTC; b) the prevalence of different mutations varies with V804M being the most frequent; c) the association genotype–phenotype is confirmed; d) by RET screening, some VUS can be found but their pathogenic role must be demonstrated before screening the family
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