TY - JOUR
T1 - Activating mutation in MET oncogene in familial colorectal cancer
AU - Neklason, Deborah W.
AU - Done, Michelle W.
AU - Sargent, Nykole R.
AU - Schwartz, Ann G.
AU - Anton-Culver, Hoda
AU - Griffin, Constance A.
AU - Ahnen, Dennis J.
AU - Schildkraut, Joellen M.
AU - Tomlinson, Gail E.
AU - Strong, Louise C.
AU - Miller, Alexander R.
AU - Stopfer, Jill E.
AU - Burt, Randall W.
N1 - Funding Information:
This project has been funded with federal funds from the National Institutes of Health, National Cancer Institute under contract RO3-CA150067, RO1-CA040641, PO1-CA073992 and sample collection was supported by Detroit Cancer Registry SEER program grant number N01-PC35145, and the Cancer Genetics Network, RFA CA-97-004, RFA-CA-97-019, and RFP N01-PC-55049-40; grants numbers U24-CA78134, U24-CA78156, U24-CA78148, U24-CA78174, U24-CA78157, U24-CA78142. Additional support was provided by a Cancer Center Support Grant P30-CA42014, Utah Cancer Registry grant HHSN 261201000026C from the National Cancer Institute’s SEER program with additional support from the Utah State Department of Health, and Utah Population Database supported by the Huntsman Cancer Foundation. This project could not have been done without the continued support from the Cancer Genetics Network who shared DNA samples and data. We acknowledge University of Utah Sequencing and Genotyping Cores. We thank Mark Yandell, Barry Moore and Hao Hu for assisting with 1000 genomes pilot data, Therese Tuohy for critical review of the manuscript, and James P. Evans, Jan T. Lowery, and Al Ziogas for their participation in CGN sample collection.
PY - 2011/10/4
Y1 - 2011/10/4
N2 - 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.
AB - 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.
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U2 - 10.1186/1471-2407-11-424
DO - 10.1186/1471-2407-11-424
M3 - Article
C2 - 21970370
AN - SCOPUS:80053559947
SN - 1471-2407
VL - 11
JO - BMC cancer
JF - BMC cancer
M1 - 424
ER -