title: Mutational Strand Asymmetries in Cancer Genomes Reveal Mechanisms of DNA Damage and Repair.
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.
authors.affiliation: 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.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Haradhvala
authors.affiliation: 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.
authors.forename: Paz
authors.initials: P
authors.lastname: Polak
authors.affiliation: Carnegie Mellon University School of Computer Science, 5000 Forbes Avenue, Pittsburgh, PA 15213, USA.
authors.forename: Petar
authors.initials: P
authors.lastname: Stojanov
authors.affiliation: Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Covington
authors.affiliation: Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Eve
authors.initials: E
authors.lastname: Shinbrot
authors.affiliation: Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA 02142, USA.
authors.forename: Julian M
authors.initials: JM
authors.lastname: Hess
authors.affiliation: 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.
authors.forename: Esther
authors.initials: E
authors.lastname: Rheinbay
authors.affiliation: Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA 02142, USA.
authors.forename: Jaegil
authors.initials: J
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Yosef E
authors.initials: YE
authors.lastname: Maruvka
authors.affiliation: Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA 02142, USA.
authors.forename: Lior Z
authors.initials: LZ
authors.lastname: Braunstein
authors.affiliation: 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.
authors.forename: Atanas
authors.initials: A
authors.lastname: Kamburov
authors.affiliation: Stanford University Department of Biology, 450 Serra Mall, Stanford, CA 94305, USA.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Hanawalt
authors.affiliation: Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Wheeler
authors.affiliation: 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.
authors.forename: Amnon
authors.initials: A
authors.lastname: Koren
authors.affiliation: Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA 02142, USA. Electronic address: lawrence@broadinstitute.org.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lawrence
authors.affiliation: 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.
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
mesh_terms: D004249:DNA Damage; D004252:DNA Mutational Analysis; D004260:DNA Repair; D004261:DNA Replication; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D014158:Transcription, Genetic