Whole genome sequencing using
massively parallel sequencing technologies enables accurate detection of
somatic rearrangements in cancer. Pinpointing large numbers of rearrangement
breakpoints to basepair 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 C>G transversions.
Source: Somatic
rearrangements across cancer reveal classes of samples with distinct patterns
of DNA breakage and rearrangement-induced hypermutability. Drier Y, Lawrence MS
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