Some cancer therapies damage DNA and cause mutations both in cancer and healthy cells of the patient. Therapy-induced mutations may underlie some of the long-term and late side effects of treatments, such as mental disabilities, organ toxicities and secondary neoplasms. Currently we ignore the mutation burden caused by different cancer treatments. Here we identify mutational signatures, or footprints of six widely-used anti-cancer therapies across more than 3,500 metastatic tumors originating from different organs. These include previously known and new mutational signatures generated by platinum-based drugs, and a novel signature of nucleoside metabolic inhibitors. Exploiting these mutational footprints, we estimate the contribution of different treatments to the mutation burden of tumors and their risk of contributing coding and potential driver mutations in the genome. The mutational footprints identified here allow for precisely Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Graphical AbstractHighlights d Somatic and germline mutation rates show a 10-bp periodicity in nucleosome-occupied DNA d This periodicity tracks DNA minor groove facing toward and away from the histones d The orientation of the periodicity depends on the mutational processes active in the tissue d This has contributed to the AT/CG 10-bp periodicity in eukaryotic genomes SUMMARYMutation rates along the genome are highly variable and influenced by several chromatin features. Here, we addressed how nucleosomes, the most pervasive chromatin structure in eukaryotes, affect the generation of mutations. We discovered that within nucleosomes, the somatic mutation rate across several tumor cohorts exhibits a strong 10 base pair (bp) periodicity. This periodic pattern tracks the alternation of the DNA minor groove facing toward and away from the histones. The strength and phase of the mutation rate periodicity are determined by the mutational processes active in tumors. We uncovered similar periodic patterns in the genetic variation among human and Arabidopsis populations, also detectable in their divergence from close species, indicating that the same principles underlie germline and somatic mutation rates. We propose that differential DNA damage and repair processes dependent on the minor groove orientation in nucleosomebound DNA contribute to the 10-bp periodicity in AT/CG content in eukaryotic genomes.

BackgroundNatural selection shapes cancer genomes. Previous studies used signatures of positive selection to identify genes driving malignant transformation. However, the contribution of negative selection against somatic mutations that affect essential tumor functions or specific domains remains a controversial topic.ResultsHere, we analyze 7546 individual exomes from 26 tumor types from TCGA data to explore the portion of the cancer exome under negative selection. Although we find most of the genes neutrally evolving in a pan-cancer framework, we identify essential cancer genes and immune-exposed protein regions under significant negative selection. Moreover, our simulations suggest that the amount of negative selection is underestimated. We therefore choose an empirical approach to identify genes, functions, and protein regions under negative selection. We find that expression and mutation status of negatively selected genes is indicative of patient survival. Processes that are most strongly conserved are those that play fundamental cellular roles such as protein synthesis, glucose metabolism, and molecular transport. Intriguingly, we observe strong signals of selection in the immunopeptidome and proteins controlling peptide exposition, highlighting the importance of immune surveillance evasion. Additionally, tumor type-specific immune activity correlates with the strength of negative selection on human epitopes.ConclusionsIn summary, our results show that negative selection is a hallmark of cell essentiality and immune response in cancer. The functional domains identified could be exploited therapeutically, ultimately allowing for the development of novel cancer treatments.Electronic supplementary materialThe online version of this article (10.1186/s13059-018-1434-0) contains supplementary material, which is available to authorized users.

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