Abstract
Cancer is a multi-faceted disease with intricate relationships between mutagenic processes, alterations in cellular signaling, and the tissue microenvironment. To date, these processes have been largely studied in isolation. A systematic understanding of how they interact and influence each other is lacking. Here, we present a framework for systematically characterizing the interaction between pairs of mutational signatures and between signatures and signaling pathway alterations. We applied this framework to large-scale data from TCGA and PCAWG and identified multiple positive and negative interactions, both cross֊tissue and tissue֊specific, that provide new insights into the molecular routes observed in tumorigenesis and their respective drivers. This framework allows for a more fine-grained dissection of common and distinct etiology of mutational signatures. We further identified several interactions with both positive and negative impacts on patient survival, demonstrating their clinical relevance and potential for improving personalized cancer care.