Summary

The past decade has witnessed the cataloging of genetic mutations in cancer genomes, providing new insights into how and in what ways cancer can develop and spread (1, 2). The focus has been on defining specific “driver” mutations, genetic errors in cancer cells that reveal basic biological processes gone awry that are required for cancer initiation and progression. These drivers are the target of new therapies—this concept is central to precision oncology efforts to treat patients according to the genetic changes that are present in their tumors (3). Along the way, it has also become apparent that cancer genomes harbor many additional “passenger” mutations (4). Patterns of driver and passenger DNA mutations derived from cancer genomes have provided clues about the different ways that cancer can manifest as a disease of genetic mutations (5, 6). In some circumstances, they can be linked to strong environmental carcinogens (for example, mutation patterns caused by tobacco smoke, ultraviolet radiation, or the fungal toxin aflatoxin) (7). Moreover, these forensic mutational patterns can be used to estimate how long it has taken for a tumor to develop (5). On page 911 of this issue, Martincorena et al. (8) turned their attention toward the detection of mutations in normal tissue, addressing a long-standing paradox that mutations arise in normal tissues but do not necessarily lead to cancer.