|Publication Type||Journal Article|
|Year of Publication||2011|
|Authors||Bass, AJ, Lawrence, MS, Brace, LE, Ramos, AH, Drier, Y, Cibulskis, K, Sougnez, C, Voet, D, Saksena, G, Sivachenko, A, Jing, R, Parkin, M, Pugh, T, Verhaak, RG, Stransky, N, Boutin, AT, Barretina, J, Solit, DB, Vakiani, E, Shao, W, Mishina, Y, Warmuth, M, Jimenez, J, Chiang, DY, Signoretti, S, Kaelin, WG, Spardy, N, Hahn, WC, Hoshida, Y, Ogino, S, Depinho, RA, Chin, L, Garraway, LA, Fuchs, CS, Baselga, J, Tabernero, J, Gabriel, S, Lander, ES, Getz, G, Meyerson, M|
Prior studies have identified recurrent oncogenic mutations in colorectal adenocarcinoma and have surveyed exons of protein-coding genes for mutations in 11 affected individuals. 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-catenin in colorectal carcinogenesis, 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.