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Cell. 2016 Jan 28;164(3):538-49. doi: 10.1016/j.cell.2015.12.050. Epub 2016 Jan 21.

Mutational Strand Asymmetries in Cancer Genomes Reveal Mechanisms of DNA Damage and Repair.

Author information

1
Massachusetts General Hospital Cancer Center and Department of Pathology, 55 Fruit Street, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA 02142, USA.
2
Massachusetts General Hospital Cancer Center and Department of Pathology, 55 Fruit Street, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA 02142, USA; Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA.
3
Carnegie Mellon University School of Computer Science, 5000 Forbes Avenue, Pittsburgh, PA 15213, USA.
4
Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
5
Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA 02142, USA.
6
Stanford University Department of Biology, 450 Serra Mall, Stanford, CA 94305, USA.
7
Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA 02142, USA; Cornell University Department of Molecular Biology and Genetics, 526 Campus Road, Ithaca, NY 14853, USA.
8
Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA 02142, USA. Electronic address: lawrence@broadinstitute.org.
9
Massachusetts General Hospital Cancer Center and Department of Pathology, 55 Fruit Street, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA 02142, USA; Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA. Electronic address: gadgetz@broadinstitute.org.

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.

PMID:
26806129
PMCID:
PMC4753048
DOI:
10.1016/j.cell.2015.12.050
[Indexed for MEDLINE]
Free PMC Article

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