Subclonal mutation selection in mouse lymphomagenesis identifies known cancer loci and suggests novel candidates

Determining whether recurrent but rare cancer mutations are bona fide driver mutations remains a bottleneck in cancer research. Here we present the most comprehensive analysis of murine leukemia virus-driven lymphomagenesis produced to date, sequencing 700,000 mutations from >500 malignancies collected at time points throughout tumor development. This scale of data allows novel statistical approaches for identifying selected mutations and yields a high-resolution, genome-wide map of the selective forces surrounding cancer gene loci. We also demonstrate negative selection of mutations that may be deleterious to tumor development indicating novel avenues for therapy. Screening of two BCL2 transgenic models confirmed known drivers of human non-Hodgkin lymphoma, and implicates novel candidates including modifiers of immunosurveillance and MHC loci. Correlating mutations with genotypic and phenotypic features independently of local variance in mutation density also provides support for weakly evidenced cancer genes. An online resource http://mulvdb.org allows customized queries of the entire dataset. Evidence implicating cancer drivers can be sparse when limited to clonal events. Here, the authors present a retrovirus driven in vivo lymphomagenesis time course including hundreds of thousands of subclonal mutations and demonstrate the utility of these in mapping the selective forces affecting cancer gene loci, including negatively selected mutations.