Identifying multigenic modules under selection in the tumor genome.

Abstract

Genomic alterations in cancer arise from selective pressures acting on hallmark molecular modules, layered over a background of random mutagenic events. Methods to detect selection at the level of modules, as opposed to genes or nucleotides, are relatively underdeveloped. Here we present CanSRMaPP (Cancer Selection Recovery by Maximum Posterior Probability), a Bayesian model of the cancer genome that infers mutational selection on single genes and multi-genic modules while simultaneously modeling background events. Applying CanSRMaPP to lung adenocarcinoma genomes, we identify positive selection on 63 modules, yielding a model that parsimoniously explains the observed pattern of genetic alterations observed in new cancer cohorts. We further show that CanSRMaPP is adaptable to more tumor types and to alternative module definitions. We show that these modules serve as an effective scaffold for translating the cancer genome to molecular states, with prediction of cancer biomarker status as demonstration. CanSRMaPP is freely available on GitHub. Supplementary Figs. S1-5, Supplementary Tables S1-5, and Supplementary Notes 1 and 2 are available at Bioinformatics online.