MOSAIC: Model-based, Subgroup-Aware Identification of Driver Mutations in Cancer

In cancer genomics, recurrent patterns of mutual exclusivity within a gene set can indicate shared biological context and involvement in tumorigenesis. However, existing methods are not designed to distinguish between mutual exclusivity arising from meaningful biological interactions from those influenced by heterogeneity between underlying patient subpopulations. In this work, we introduce MOSAIC, a novel statistical framework that models patient subgroup heterogeneity in mutual exclusivity analyses. In experiments with simulated data and real data from The Cancer Genome Atlas, we show that MOSAIC amplifies subgroup-specific mutual exclusivity signals, including between IDH1 and IDH2 in young low grade glioma patients, while reducing the effect of signals produced by underlying subgroup structures, such as distinct genomic lineages associated with histological subtypes of endometrial cancer. Finally, we demonstrate that MOSAIC is more powerful than existing p -value combination methods for patient subgroup stratification. MOSAIC is available as an open-source tool at https://github.com/reynalab/mosaic .