Mutational Strand Asymmetries in Cancer Genomes Reveal Mechanisms of DNA Damage and Repair.
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Abstract | Mutational processes constantly shape the somatic genome, leading to immunity, aging, cancer, and other diseases. When cancer is the outcome, we are afforded a glimpse into these processes by the clonal expansion of the malignant cell. Here, we characterize a less explored layer of the mutational landscape of cancer: mutational asymmetries between the two DNA strands. Analyzing whole-genome sequences of 590 tumors from 14 different cancer types, we reveal widespread asymmetries across mutagenic processes, with transcriptional ("T-class") asymmetry dominating UV-, smoking-, and liver-cancer-associated mutations and replicative ("R-class") asymmetry dominating POLE-, APOBEC-, and MSI-associated mutations. We report a striking phenomenon of transcription-coupled damage (TCD) on the non-transcribed DNA strand and provide evidence that APOBEC mutagenesis occurs on the lagging-strand template during DNA replication. As more genomes are sequenced, studying and classifying their asymmetries will illuminate the underlying biological mechanisms of DNA damage and repair. |
Year of Publication | 2016
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Journal | Cell
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Volume | 164
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Issue | 3
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Pages | 538-49
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Date Published | 2016 Jan 28
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ISSN | 1097-4172
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URL | |
DOI | 10.1016/j.cell.2015.12.050
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PubMed ID | 26806129
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PubMed Central ID | PMC4753048
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Grant list | U54 HG003067 / HG / NHGRI NIH HHS / United States
U54HG003273 / HG / NHGRI NIH HHS / United States
U54HG003067 / HG / NHGRI NIH HHS / United States
U24 CA143845 / CA / NCI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
R01 CA077712 / CA / NCI NIH HHS / United States
U24CA143845 / CA / NCI NIH HHS / United States
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