title: Somatic rearrangements across cancer reveal classes of samples with distinct patterns of DNA breakage and rearrangement-induced hypermutability.
abstract: Whole-genome sequencing using massively parallel sequencing technologies enables accurate detection of somatic rearrangements in cancer. Pinpointing large numbers of rearrangement breakpoints to base-pair resolution allows analysis of rearrangement microhomology and genomic location for every sample. Here we analyze 95 tumor genome sequences from breast, head and neck, colorectal, and prostate carcinomas, and from melanoma, multiple myeloma, and chronic lymphocytic leukemia. We discover three genomic factors that are significantly correlated with the distribution of rearrangements: replication time, transcription rate, and GC content. The correlation is complex, and different patterns are observed between tumor types, within tumor types, and even between different types of rearrangements. Mutations in the APC gene correlate with and, hence, potentially contribute to DNA breakage in late-replicating, low %GC, untranscribed regions of the genome. We show that somatic rearrangements display less microhomology than germline rearrangements, and that breakpoint loci are correlated with local hypermutability with a particular enrichment for   transversions.
authors.affiliation: Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Yotam
authors.initials: Y
authors.lastname: Drier
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lawrence
authors.forename: Scott L
authors.initials: SL
authors.lastname: Carter
authors.forename: Chip
authors.initials: C
authors.lastname: Stewart
authors.forename: Stacey B
authors.initials: SB
authors.lastname: Gabriel
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lander
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
mesh_terms: D001482:Base Composition; D019457:Chromosome Breakage; D056905:Chromosome Breakpoints; D019295:Computational Biology / Q000379:methods; D004261:DNA Replication; D006801:Humans; D009154:Mutation; D059645:Mutation Rate; D009369:Neoplasms / Q000235:genetics*; D011995:Recombination, Genetic; D014158:Transcription, Genetic