Whole Exome Sequencing Identifies a Germline MET Mutation in Two Siblings With Hereditary Wild-Type RET Medullary Thyroid Cancer

Hum Mutat. 2018 Mar;39(3):371-377. doi: 10.1002/humu.23378. Epub 2017 Dec 20.


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.

Keywords: MET proto-oncogene; RET proto-oncogene; familial medullary thyroid cancer; medullary thyroid cancer; whole exome sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Carcinoma, Neuroendocrine / genetics*
  • Female
  • Germ Cells / metabolism*
  • Humans
  • Male
  • Mutation / genetics*
  • Pedigree
  • Proto-Oncogene Proteins c-met / genetics*
  • Proto-Oncogene Proteins c-ret / genetics*
  • Siblings*
  • Thyroid Neoplasms / genetics*
  • Whole Exome Sequencing*


  • Proto-Oncogene Proteins c-met
  • Proto-Oncogene Proteins c-ret
  • RET protein, human

Supplementary concepts

  • Thyroid cancer, medullary