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The analysis of the mutational landscape of cancer, including mutualexclusivity and co-occurrence of mutations, has been instrumental in studyingthe disease. We hypothesized that exploring the interplay betweenco-occurrence, mutual exclusivity, and functional interactions between geneswill further improve our understanding of the disease and help to uncover newrelations between cancer driving genes and pathways. To this end, we designed ageneral framework, BeWith, for identifying modules with different combinationsof mutation and interaction patterns. We focused on three different settings ofthe BeWith schema: (i) BeME-WithFun in which the relations between modules areenriched with mutual exclusivity while genes within each module arefunctionally related; (ii) BeME-WithCo which combines mutual exclusivitybetween modules with co-occurrence within modules; and (iii) BeCo-WithMEFunwhich ensures co-occurrence between modules while the within module relationscombine mutual exclusivity and functional interactions. We formulated theBeWith framework using Integer Linear Programming (ILP), enabling us to findoptimally scoring sets of modules. Our results demonstrate the utility ofBeWith in providing novel information about mutational patterns, driver genes,and pathways. In particular, BeME-WithFun helped identify functionally coherentmodules that might be relevant for cancer progression. In addition to findingpreviously well-known drivers, the identified modules pointed to the importanceof the interaction between NCOR and NCOA3 in breast cancer. Additionally, anapplication of the BeME-WithCo setting revealed that gene groups differ withrespect to their vulnerability to different mutagenic processes, and helped usto uncover pairs of genes with potentially synergetic effects, including apotential synergy between mutations in TP53 and metastasis related DCC gene.

plos computational biology/plos computational biology

BeWith: A Between-Within Method to Discover Relationships between Cancer  Modules via Integrated Analysis of Mutual Exclusivity, Co-occurrence and  Functional Interactions