Activating mutation in MET oncogene in familial colorectal cancer

BMC Cancer

Research Article

Jill E Stopfer¹  Joellen M Schildkraut²  Hoda Anton-Culver³  Dennis J Ahnen⁴  Louise C Strong⁵  Gail E Tomlinson⁶  Alexander R Miller⁷  Constance A Griffin⁸  Michelle W Done⁹  Randall W Burt^1,10  Nykole R Sargent^1,11  Deborah W Neklason^1,11  Ann G Schwartz^1,12 

[1] Abramson Cancer Center, University of Pennsylvania, Pennsylvania, Philadelphia, USA;Department of Community and Family Medicine, Duke University, Durham, North Carolina, USA;Department of Epidemiology, University of California Irvine, Irvine, California, USA;Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA;Department of Molecular Genetics, University of Texas M.D. Anderson Medical Center, Houston, Texas, USA;Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA;Department of Surgical Oncology, START Center for Cancer Care, San Antonio, Texas, USA;Departments of Pathology and Oncology, Johns Hopkins University, Baltimore, Maryland, USA;Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA;Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA;Department of Medicine, University of Utah, Salt Lake City, Utah, USA;Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA;Department of Oncological Sciences, University of Utah, Salt Lake City, Utah, USA;Karmanos Cancer Institute, Department of Medicine, Wayne State University, Detroit, Michigan, USA;

关键词: Germline Mutation;    Lynch Syndrome;    Sibling Pair;    TaqMan Assay;    Meet Gene;   

DOI  :  10.1186/1471-2407-11-424

 received in 2011-07-09, accepted in 2011-10-04,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundIn 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.MethodsMET 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.ResultsHere 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.ConclusionsAlthough 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.

【 授权许可】

CC BY   
© Neklason et al; licensee BioMed Central Ltd. 2011