Premium
Whole exome sequencing identifies a germline MET mutation in two siblings with hereditary wild‐type RET medullary thyroid cancer
Author(s) -
Sponziello Marialuisa,
Benvenuti Silvia,
Gentile Alessandra,
Pecce Valeria,
Rosignolo Francesca,
Virzì Anna Rita,
Milan Melissa,
Comoglio Paolo M.,
Londin Eric,
Fortina Paolo,
Barnabei Agnese,
Appetecchia Marialuisa,
Marandino Ferdinando,
Russo Diego,
Filetti Sebastiano,
Durante Cosimo,
Verrienti Antonella
Publication year - 2018
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23378
Subject(s) - biology , medullary thyroid cancer , exome sequencing , cancer research , germline mutation , germline , mutation , cabozantinib , exome , ret proto oncogene , receptor tyrosine kinase , ectopic expression , cancer , genetics , proto oncogene proteins c ret , multiple endocrine neoplasia type 2 , thyroid cancer , receptor , gene , neurotrophic factors , glial cell line derived neurotrophic factor
Whole exome sequencing (WES) was used to investigate two Italian siblings with wild‐type RET genotype, who developed medullary thyroid cancers (MTCs) and, later, primary prostate and breast cancers, respectively. The proband's MTC harbored a p.Met918Thr RET mutation; his sister's MTC was RET / RAS wild‐type. Both siblings had a germline mutation (p.Arg417Gln) in the extracellular Sema domain of the proto‐oncogene MET . Experiments involving ectopic expression of MET p.Arg417Gln in MET ‐negative T47D breast cancer cells documented the mutant receptor's functionality and its ability to enhance cell migration and invasion. Our findings highlight a possible link between MET germline mutations and MTCs and suggest that MET p. Arg417Gln may promote an invasive malignant phenotype. The possibility that MTC can be driven/co‐driven by a MET mutation has potential management implications, since the tyrosine‐kinase inhibitor cabozantinib—approved for treating advanced MTCs—is a specific MET inhibitor.