Systematic interrogation of mutation groupings reveals divergent downstream expression programs within key cancer genes

ABSTRACT Genes implicated in tumorigenesis often exhibit diverse sets of genomic variants in the tumor cohorts within which they are frequently mutated. We sought to identify the downstream expression effects of these perturbations and to find whether or not this heterogeneity at the genomic level is reflected in a corresponding heterogeneity at the transcriptomic level. Applying a novel hierarchical framework for organizing the mutations present in a cohort along with machine learning pipelines trained on sample expression profiles we systematically interrogated the signatures associated with combinations of perturbations recurrent in cancer. This allowed us to catalogue the mutations with discernible downstream expression effects across a number of tumor cohorts as well as to uncover and characterize a multitude of cases where subsets of a genes mutations are clearly divergent in their function from the remaining mutations of the gene.