Twenty-Five Years Experience on RET Genetic Screening on Hereditary MTC: An Update on The Prevalence of Germline RET Mutations

Pathogenic germline mutations affecting the proto-oncogene underlie the development of hereditary medullary thyroid carcinoma (MTC). The aims of this study were to evaluate the prevalence of germline mutations in a large series of MTC, collected over the last 25 years, and to reappraise their clinic...

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Bibliographic Details
Published in:Genes 2019-09, Vol.10 (9), p.698
Main Authors: Elisei, Rossella, Tacito, Alessia, Ramone, Teresa, Ciampi, Raffaele, Bottici, Valeria, Cappagli, Virginia, Viola, David, Matrone, Antonio, Lorusso, Loredana, Valerio, Laura, Giani, Carlotta, Campopiano, Cristina, Prete, Alessandro, Agate, Laura, Molinaro, Eleonora, Romei, Cristina
Format: Article
Language:English
Subjects:
Carcinoma, Medullary - congenital
Carcinoma, Medullary - genetics
Disease
Female
Genetic disorders
Genetic screening
Genotypes
Germ-Line Mutation
Humans
Kinases
Ligands
Male
Medical prognosis
Multiple Endocrine Neoplasia Type 2a - genetics
Mutation
Mutation Rate
Phenotypes
Proto-Oncogene Proteins c-ret - genetics
Ret protein
Thyroid cancer
Thyroid carcinoma
Thyroid Neoplasms - genetics
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Summary:Pathogenic germline mutations affecting the proto-oncogene underlie the development of hereditary medullary thyroid carcinoma (MTC). The aims of this study were to evaluate the prevalence of germline mutations in a large series of MTC, collected over the last 25 years, and to reappraise their clinical significance. We performed genetic screening in 2031 Italian subjects: patients who presented with sporadic (n = 1264) or hereditary (n = 117) MTC, plus 650 relatives. A 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. a) 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 screening, some VUS can be found but their pathogenic role must be demonstrated before screening the family.
ISSN:2073-4425
2073-4425
DOI:10.3390/genes10090698