title: Mutation signatures of carcinogen exposure: genome-wide detection and new opportunities for cancer prevention.
abstract: Exposure to environmental mutagens is an important cause of human cancer, and measures to reduce mutagenic and carcinogenic exposures have been highly successful at controlling cancer. Until recently, it has been possible to connect the chemical characteristics of mutagens to actual mutations observed in human tumors only indirectly. Now, next-generation sequencing technology enables us to observe in detail the DNA-sequence-level effects of well-known mutagens, such as ultraviolet radiation and tobacco smoke, as well as endogenous mutagenic processes, such as those involving activated DNA cytidine deaminases (APOBECs). We can also observe the effects of less well-known but potent mutagens, including those recently found to be present in some herbal remedies. Crucially, we can now tease apart the superimposed effects of several mutational exposures and processes and determine which ones occurred during the development of individual tumors. Here, we review advances in detecting these mutation signatures and discuss the implications for surveillance and prevention of cancer. The number of sequenced tumors from diverse cancer types and multiple geographic regions is growing explosively, and the genomes of these tumors will bear the signatures of even more diverse mutagenic exposures. Thus, we envision development of wide-ranging compendia of mutation signatures from tumors and a concerted effort to experimentally elucidate the signatures of a large number of mutagens. This information will be used to link signatures observed in tumors to the exposures responsible for them, which will offer unprecedented opportunities for prevention.
authors.affiliation: Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610, Singapore ; Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
authors.forename: Song Ling
authors.initials: SL
authors.lastname: Poon
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore ; Duke-NUS Centre for Computational Biology, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
authors.forename: John R
authors.initials: JR
authors.lastname: McPherson
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore ; Division of Cellular and Molecular Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610, Singapore ; Cancer Science Institute of Singapore, National University of Singapore, Centre for Life Sciences, 28 Medical Drive, Singapore 117456, Singapore ; Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.
authors.forename: Patrick
authors.initials: P
authors.lastname: Tan
authors.affiliation: Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610, Singapore ; Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
authors.forename: Bin Tean
authors.initials: BT
authors.lastname: Teh
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore ; Duke-NUS Centre for Computational Biology, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Rozen