Integrated Multi-omics Data Analyses for Exploring the Co-occurring and Mutually Exclusive Gene Alteration Events in Colorectal Cancer.

Co-occurring and mutually exclusive gene alteration events are helpful for understanding carcinogenesis but systematic screening for such events is quite limited. We conducted pairwise screening tests to identify "hit pairs" in colorectal cancer (CRC) by utilizing the cross-omics data from The Cancer Genome Atlas (TCGA). Numerous hit pairs involving somatic mutations, copy number variations, and DNA methylation were found to occur nonrandomly in CRC, such asKRASandHOXB6, SMAD4andPMEPA1. Based on these hit pairs, we identified 32 synthetic lethal pairs and 7,527 co-occurring pairs relating to drug response. Our further biological experiments showed that the co-occurrence of mutantFCGBPandNUDT12silencing (or mutantTMC3andRPS6KA6silencing) with small interfering RNA reduced cell viability. Moreover, novel hit pairs could influence prognosis. The patients who carried concurrent mutations ofIRF5andNEFH, SYNE1andTTN, orMUC16andNEFHhad worse survival outcomes. Particularly, the presence of mutantSYNE1andTTNpair not only affects prognosis, but also is related to CRC patients' response to drug treatment. Our "hit pair" genes may provide insights into colorectal carcinogenesis and help open new avenues for CRC therapy.