Looking beyond drivers and passengers in cancer genome sequencing data.

Cancer arises as a result of acquired changes in the DNA sequence of the genome of somatic cells. A subset of the genetic changes, dubbed driver mutations, propels tumor growth, and the remaining changes are passengers, apparently inconsequential for neoplastic transformation. Massive genome sequencing of thousands of tumors from all major cancer types has enabled cataloging of the so-called driver and passenger mutations, and facilitated molecular classification of cancer, guiding precision medicine approach for the patients. Nonetheless, innovative analyses of cancer genomics data has led to novel, sometimes serendipitous findings that have aided to our understanding of other aspects of the biology of the disease and opened up new frontiers. For instance, emerging findings show that mutational patterns in cancer genomes can help detect signatures of known and novel DNA damage and repair processes, provide a likely chronological account of genomic changes in cancer genomes, and allow revisiting the models of cancer evolution. These findings have stimulated original approaches to identify disease etiology, stratify patients, target the disease, and monitor patient responses, complementing driver-mutation centric approaches. In this review, we discuss these emerging approaches and unexpected breakthroughs, and their implications for basic cancer research and clinical practices.