Co-mutation and exclusion analysis in human tumors, a means for cancer biology studies and treatment design

Abstract

BackgroundMalignant tumors originate from genomic and epigenomic alterations, which lead to loss of control of the cellular circuitry. These alterations relate with each other in patterns of mutual exclusion and co-occurrence that affect prognosis and treatment response and highlight the need for multitargeted therapy. However, to the best of our knowledge, there are no systematic reports in the literature of co-dependent and mutually exclusive mutations across all types of cancer. In addition, the studies reported so far generally deal with whole genes instead of specific mutations, ignoring the fact that different alterations in the same gene can have widely different effects.\n\nResultsHere we present a systematic analysis of co-dependencies of somatic mutations across all cancer types. Combining multi testing with conditional and expected mutational probabilities, we have found pairs and networks of co-mutations and exclusions, some of them in particular types of cancer and others widespread. We have also determined that driver loci are present in more types of cancer than non driver loci, that they tend to pair within a single gene and that those pairs are more often exclusions than co-mutations.\n\nConclusionsBased on this properties, we propose new drivers that warrant experimental validation. Our analysis is potentially relevant for cancer biology and classification, as well as for the rational selection of multitargeted therapeutic approaches.