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

Marialuisa Sponziello, Silvia Benvenuti, Alessandra Gentile, Valeria Pecce, Francesca Rosignolo, Anna Rita Virzì, Melissa Milan, Paolo M. Comoglio, Eric Londin, Paolo Fortina, Agnese Barnabei, Marialuisa Appetecchia, Ferdinando Marandino, Diego Russo, Sebastiano Filetti, Cosimo Durante, Antonella Verrienti

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)371-377
Number of pages7
JournalHuman Mutation
Volume39
Issue number3
DOIs
Publication statusPublished - Mar 1 2018

Keywords

  • familial medullary thyroid cancer
  • medullary thyroid cancer
  • MET proto-oncogene
  • RET proto-oncogene
  • whole exome sequencing

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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