A molecular taxonomy of tumors independent of tissue-of-origin

Abstract Cancer is an organism-level disease, impacting processes from cellular metabolism and the microenvironment to systemic immune response. Nevertheless, efforts to distinguish overarching mutational processes from interactions with the cell of origin for a tumor have seen limited success, presenting a barrier to individualized medicine. Here we present a pathway-centric approach, extracting somatic mutational profiles within and between tissues, largely orthogonal to cell of origin, mutational burden, or stage. Known predisposition variants are equally distributed among clusters, and largely independent