TY - JOUR
T1 - Whole exome sequencing identifies a germline MET mutation in two siblings with hereditary wild-type RET medullary thyroid cancer.
AU - Sponziello, Marialuisa
AU - Benvenuti, Silvia
AU - Gentile, Alessandra
AU - Pecce, Valeria
AU - Rosignolo, Francesca
AU - Virzi, Anna Rita
AU - Milan, Melissa
AU - Comoglio, Paolo M.
AU - Londin, Eric
AU - Fortina, Paolo
AU - Barnabei, Agnese
AU - Appetecchia, Marialuisa
AU - Marandino, Ferdinando
AU - Russo, Diego
AU - Filetti, Sebastiano
AU - Durante, Cosimo
AU - Verrienti, Antonella
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
KW - MET proto-oncogene, RET proto-oncogene, familial medullary thyroid cancer, medullary thyroid cancer, whole exome sequencing
M3 - Article
JO - Human Mutation
JF - Human Mutation
SN - 1059-7794
ER -