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.
Whole exome sequencing identifies a germline MET mutation in two siblings with hereditary wild-type RET medullary thyroid cancer / 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. - In: HUMAN MUTATION. - ISSN 1059-7794. - STAMPA. - 39:3(2018), pp. 371-377. [10.1002/humu.23378]
Whole exome sequencing identifies a germline MET mutation in two siblings with hereditary wild-type RET medullary thyroid cancer
Sponziello, Marialuisa;Pecce, Valeria;Rosignolo, Francesca;Fortina, Paolo;Filetti, Sebastiano;Durante, Cosimo
;Verrienti, Antonella
2018
Abstract
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.File | Dimensione | Formato | |
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