Abstract
Current tailored-therapy efforts in cancer are largely focused on a small number of highly recurrently mutated driver genes but therapeutic targeting of these oncogenes remains challenging. However, the vast number of genes mutated infrequently across cancers has received less attention, in part, due to a lack of understanding of their biological significance. We present SYSMut, an extendable systems biology platform that can robustly infer the biologic consequences of somatic mutations by integrating routine multiomics profiles in primary tumors. We establish SYSMut's improved performance vis-à-vis state-of-the-art driver gene identification methodologies by recapitulating the functional impact of known driver genes, while additionally identifying novel functionally impactful mutated genes across 29 cancers. Subsequent application of SYSMut on low-frequency gene mutations in head and neck squamous cell (HNSC) cancers, followed by molecular and pharmacogenetic validation, revealed the lipidogenic network as a novel therapeutic vulnerability in aggressive HNSC cancers. SYSMut is thus a robust scalable framework that enables the discovery of new targetable avenues in cancer.