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Whole exome sequencing identifies a germline MET mutation in two siblings with hereditary wild-type RET medullary thyroid cancer.

Whole exome sequencing identifies a germline MET mutation in two siblings with hereditary wild-type RET medullary thyroid cancer.
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Sponziello M, Benvenuti S, Gentile A, Pecce V, Rosignolo F, Virzì AR, Milan M, Comoglio PM, Londin E, Fortina P, Barnabei A, Appetecchia M, Marandino F, Russo D, Filetti S, Durante C, Verrienti A,


Sponziello M, Benvenuti S, Gentile A, Pecce V, Rosignolo F, Virzì AR, Milan M, Comoglio PM, Londin E, Fortina P, Barnabei A, Appetecchia M, Marandino F, Russo D, Filetti S, Durante C, Verrienti A, (click to view)

Sponziello M, Benvenuti S, Gentile A, Pecce V, Rosignolo F, Virzì AR, Milan M, Comoglio PM, Londin E, Fortina P, Barnabei A, Appetecchia M, Marandino F, Russo D, Filetti S, Durante C, Verrienti A,

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Human mutation 2017 12 08() doi 10.1002/humu.23378

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. This article is protected by copyright. All rights reserved.

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