Journal
CELL
Volume 164, Issue 3, Pages 538-549Publisher
CELL PRESS
DOI: 10.1016/j.cell.2015.12.050
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Funding
- NIH TCGA Genome Data Analysis Center [U24CA143845]
- NHGRI Genome Sequencing Center [U54HG003067]
- NHGRI [U54HG003273]
- G.G.'s startup funds at MGH
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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.
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