Phase and context shape the function of composite oncogenic mutations

Cancers develop as a result of driver mutations(1,2) that lead to clonal outgrowth and disease evolution(3,4). The discovery and functional characterization of individual driver mutations is a central aim of cancer research and has elucidated myriad phenotypes(5) and therapeutic vulnerabilities(6). Serial genetic evolution of mutant cancer genes(7,8) and the allelic context in which they arise, however, is poorly understood in both common and rare cancer genes and tumor types. Here, we find that nearly 1 in 4 human tumors harbor a composite mutation of a cancer-associated gene, defined as two nonsynonymous somatic mutations in the same gene and tumor. Composite mutations are enriched in specific genes, have an elevated rate of utilization of less common hotspot mutations acquired in a chronology driven in part by oncogenic fitness, and arise in an allelic configuration that reflects context-specific selective pressures. Cis-acting composite mutations are hypermorphic in some genes, such as TERT, where dosage effects predominate, while they lead to selection of function in others such as TP53. Collectively, composite mutations are driver alterations that arise from context- and allele-specific selective pressures dependent in part on gene and mutation function leading to complex, often neomorphic functions of biological and therapeutic significance.