Zaidi SH, Harrison TA, Phipps AI, Steinfelder R, Trinh QM, Qu C, Banbury BL, Georgeson P, Grasso CS, Giannakis M, Adams JB, Alwers E, Amitay EL, Barfield RT, Berndt SI, Borozan I, Brenner H, Brezina S, Buchanan DD, Cao Y, Chan AT, Chang-Claude J, Connolly CM, Drew DA, Farris AB, Figueiredo JC, French AJ, Fuchs CS, Garraway LA, Gruber S, Guinter MA, Hamilton SR, Harlid S, Heisler LE, Hidaka A, Hopper JL, Huang WY, Huyghe JR, Jenkins MA, Krzyzanowski PM, Lemire M, Lin Y, Luo X, Mardis ER, McPherson JD, Miller JK, Moreno V, Mu XJ, Nishihara R, Papadopoulos N, Pasternack D, Quist MJ, Rafikova A, Reid EEG, Shinbrot E, Shirts BH, Stein LD, Teney CD, Timms L, Um CY, Van Guelpen B, Van Tassel M, Wang X, Wheeler DA, Yung CK, Hsu L, Ogino S, Gsur A, Newcomb PA, Gallinger S, Hoffmeister M, Campbell PT, Thibodeau SN, Sun W, Hudson TJ, Peters U

Colorectal cancer (CRC) is a biologically heterogeneous disease. To characterize its mutational profile, we conduct targeted sequencing of 205 genes for 2,105 CRC cases with survival data. Our data shows several findings in addition to enhancing the existing knowledge of CRC. We identify PRKCI, SPZ1, MUTYH, MAP2K4, FETUB, and TGFBR2 as additional genes significantly mutated in CRC. We find that among hypermutated tumors, an increased mutation burden is associated with improved CRC-specific survival (HR = 0.42, 95% CI: 0.21-0.82). Mutations in TP53 are associated with poorer CRC-specific survival, which is most pronounced in cases carrying TP53 mutations with predicted 0% transcriptional activity (HR = 1.53, 95% CI: 1.21-1.94). Furthermore, we observe differences in mutational frequency of several genes and pathways by tumor location, stage, and sex. Overall, this large study provides deep insights into somatic mutations in CRC, and their potential relationships with survival and tumor features.