Abstract
Prior studies have identified recurrent oncogenic mutations in colorectal adenocarcinoma1 and have surveyed exons of protein-coding genes for mutations in 11 affected individuals2,3. Here we report whole-genome sequencing from nine individuals with colorectal cancer, including primary colorectal tumors and matched adjacent non-tumor tissues, at an average of 30.7× and 31.9× coverage, respectively. We identify an average of 75 somatic rearrangements per tumor, including complex networks of translocations between pairs of chromosomes. Eleven rearrangements encode predicted in-frame fusion proteins, including a fusion of VTI1A and TCF7L2 found in 3 out of 97 colorectal cancers. Although TCF7L2 encodes TCF4, which cooperates with β-catenin4 in colorectal carcinogenesis5,6, the fusion lacks the TCF4 β-catenin–binding domain. We found a colorectal carcinoma cell line harboring the fusion gene to be dependent on VTI1A-TCF7L2 for anchorage-independent growth using RNA interference-mediated knockdown. This study shows previously unidentified levels of genomic rearrangements in colorectal carcinoma that can lead to essential gene fusions and other oncogenic events.
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Acknowledgements
We thank all members of the Biological Samples Platform and DNA Sequencing Platforms of the Broad Institute, without whose work this sequencing project could not have occurred, and R. Shivdasani and M. Freedman for helpful discussion. This work was supported by US National Institutes of Health grant K08CA134931 (A.J.B.), a GI SPORE Developmental Project Award (P50CA127003; M.M.) and the National Human Genome Research Institute (E.S.L.).
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A.J.B., M.S.L., A.H.R., Y.D., K.C., A.S., T.P., R.J., D.V., G.S., R.G.V. and N. Stransky performed computational analysis. J. Barretina, J. Baselga, J.J., J.T., D.B.S., E.V., D.Y.C., W.G.K. and S.S. provided samples for analysis. A.J.B., L.E.B., Y.M. and W.S. performed laboratory experiments. A.T.B., Y.H., M.W., N.S., R.A.D., W.C.H., C.S.F. and S.O. provided expert guidance regarding the analysis. C.S., M.P., L.C., L.A.G., S.G. and E.S.L. supervised and designed the sequencing effort. A.J.B., M.S.L., E.S.L., G.G. and M.M. designed the study, analyzed the data and prepared the manuscript. All coauthors reviewed and commented on the manuscript.
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M.M., L.A.G. and E.S.L. are equity-holding founding advisors of Foundation Medicine. M.M. and L.A.G. consult for Novartis. M.M. is also a patent holder on the use of EGFR mutations in lung cancer licensed to Genzyme Genetics. W.S., Y.M. and M.W. are employees of Novartis.
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Supplementary Text and Figures
Supplementary Figures 1 and 2, Supplementary Tables 2, 3 and 5 and Supplementary Note. (PDF 882 kb)
Supplementary Table 1
Non-synonymous Mutations and Insertions/Deletions Identified Within Coding Genes (XLSX 185 kb)
Supplementary Table 4
Somatic Rearrangements Identified with dRanger Algorithm (XLSX 146 kb)
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Bass, A., Lawrence, M., Brace, L. et al. Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion. Nat Genet 43, 964–968 (2011). https://doi.org/10.1038/ng.936
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DOI: https://doi.org/10.1038/ng.936
