title: Activating mutation in MET oncogene in familial colorectal cancer.
abstract: BACKGROUND
  In developed countries, the lifetime risk of developing colorectal cancer (CRC) is 5%, and it is the second leading cause of death from cancer. The presence of family history is a well established risk factor with 25-35% of CRCs attributable to inherited and/or familial factors. The highly penetrant inherited colon cancer syndromes account for approximately 5%, leaving greater than 20% without clear genetic definition. Familial colorectal cancer has been linked to chromosome 7q31 by multiple affected relative pair studies. The MET proto-oncogene which resides in this chromosomal region is considered a candidate for genetic susceptibility.
  
  
  METHODS
  MET exons were amplified by PCR from germline DNA of 148 affected sibling pairs with colorectal cancer. Amplicons with altered sequence were detected with high-resolution melt-curve analysis using a LightScanner (Idaho Technologies). Samples demonstrating alternative melt curves were sequenced. A TaqMan assay for the specific c.2975C >T change was used to confirm this mutation in a cohort of 299 colorectal cancer cases and to look for allelic amplification in tumors.
  
  
  RESULTS
  Here we report a germline non-synonymous change in the MET proto-oncogene at amino acid position T992I (also reported as MET p.T1010I) in 5.2% of a cohort of sibling pairs affected with CRC. This genetic variant was then confirmed in a second cohort of individuals diagnosed with CRC and having a first degree relative with CRC at prevalence of 4.1%. This mutation has been reported in cancer cells of multiple origins, including 2.5% of colon cancers, and in <1% in the general population. The threonine at amino acid position 992 lies in the tyrosine kinase domain of MET and a change to isoleucine at this position has been shown to promote metastatic behavior in cell-based models. The average age of CRC diagnosis in patients in this study is 63 years in mutation carriers, which is 8 years earlier than the general population average for CRC.
  
  
  CONCLUSIONS
  Although the MET p.T992I genetic mutation is commonly found in somatic colorectal cancer tissues, this is the first report also implicating this MET genetic mutation as a germline inherited risk factor for familial colorectal cancer. Future studies on the cancer risks associated with this mutation and the prevalence in different at-risk populations will be an important extension of this work to define the clinical significance.
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA. deb.neklason@hci.utah.edu
authors.forename: Deborah W
authors.initials: DW
authors.lastname: Neklason
authors.forename: Michelle W
authors.initials: MW
authors.lastname: Done
authors.forename: Nykole R
authors.initials: NR
authors.lastname: Sargent
authors.forename: Ann G
authors.initials: AG
authors.lastname: Schwartz
authors.forename: Hoda
authors.initials: H
authors.lastname: Anton-Culver
authors.forename: Constance A
authors.initials: CA
authors.lastname: Griffin
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Ahnen
authors.forename: Joellen M
authors.initials: JM
authors.lastname: Schildkraut
authors.forename: Gail E
authors.initials: GE
authors.lastname: Tomlinson
authors.forename: Louise C
authors.initials: LC
authors.lastname: Strong
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Miller
authors.forename: Jill E
authors.initials: JE
authors.lastname: Stopfer
authors.forename: Randall W
authors.initials: RW
authors.lastname: Burt
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics*; D005091:Exons; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D035781:Siblings
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met