Characterizing Mutually Exclusive Driver Mutations in Pan-Cancer

Efforts on cancer genomic study have revealed that mutations in cancer-driving oncogenes tend to mutually exclusive. To understand this tumorigenic mechanism and common cancer features, large-scale genomic study and molecular analyses across many cancer types are essential. We compiled somatic mutation and transcriptome profiles for a pan-cancer dataset that contains tumor tissue samples from 32 cancer types for over 10,000 patients. The genomic and molecular analysis was applied to four pan-cancer subgroups including pan-gastrointestinal, pan-gynecological, pan-kidney and pan-squamous, as well as the entire patient group. We identified seven genes, TP53, PIK3CA, PTEN, PIK3R1, LRP1B, CDH1, and TRRAP exhibited mutually exclusive mutation patterns across all cancer types (adjusted ). The mutations in these genes occurred in 55.9% of all cancer patients and over 70% of patients with pan-gastrointestinal, pan-gynecological and pan-squamous. Excepting LRP1B, the other six genes are included in the known cancer pathways. Notably, TP53, PIK3CA, and PIK3R1 are involved in over 20 cancer-related pathways. The co-expression network analysis suggested that LRP1B was associated with multiple genes that showed significant enrichment in Wnt signal pathway (adjusted p=0.0023) and ERBB signal pathway (adjusted p=0.0097). We further constructed a regulatory network to infer novel regulations of LRP1B in cancer. In addition, based on the mutations in the seven genes, we divided the patients into different groups for survival analysis. We found that the survival rate of the patient group with TP53 mutations was significantly shorter than in other groups (log rank p = 5.88e-10) in pan-gynecological. Our analysis systematically revealed the mutually exclusive mutation patterns of seven cancer genes across 32 cancer types. It helps us to better understanding the relations among different cancer types and pan-cancer subgroups, providing new insights into common mechanisms underlying diverse cancer types.