Somatic rearrangements across cancer reveal classes of samples with distinct patterns of DNA breakage and rearrangement-induced hypermutability

Yotam Drier, Michael S. Lawrence, Scott L. Carter, Chip Stewart, Stacey B. Gabriel, Eric S. Lander, Matthew Meyerson, Rameen Beroukhim, Gad Getz*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

103 Scopus citations

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 C4G transversions.

Original languageAmerican English
Pages (from-to)228-235
Number of pages8
JournalGenome Research
Volume23
Issue number2
DOIs
StatePublished - Feb 2013
Externally publishedYes

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