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

Nicholas J Haradhvala; Paz Polak; Petar Stojanov; Kyle R Covington; Eve Shinbrot; Julian M Hess; Esther Rheinbay; Jaegil Kim; Yosef E Maruvka; Lior Z Braunstein; Atanas Kamburov; Philip C Hanawalt; David A Wheeler; Amnon Koren; Michael S Lawrence; Gad Getz

doi:10.1016/j.cell.2015.12.050

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

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

Authors

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

DNA Damage*
DNA Mutational Analysis*
DNA Repair*
DNA Replication
Genome, Human
Genome-Wide Association Study
Humans
Mutation
Neoplasms / genetics*
Neoplasms / pathology
Transcription, Genetic

Abstract

Publication types

MeSH terms

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