title: DNA replication timing and long-range DNA interactions predict mutational landscapes of cancer genomes.
abstract: Somatic copy-number alterations (SCNA) are a hallmark of many cancer types, but the mechanistic basis underlying their genome-wide patterns remains incompletely understood. Here we integrate data on DNA replication timing, long-range interactions between genomic material, and 331,724 SCNAs from 2,792 cancer samples classified into 26 cancer types. We report that genomic regions of similar replication timing are clustered spatially in the nucleus, that the two boundaries of SCNAs tend to be found in such regions, and that regions replicated early and late display distinct patterns of frequencies of SCNA boundaries, SCNA size and a preference for deletions over insertions. We show that long-range interaction and replication timing data alone can identify a significant proportion of SCNAs in an independent test data set. We propose a model for the generation of SCNAs in cancer, suggesting that data on spatial proximity of regions replicating at the same time can be used to predict the mutational landscapes of cancer genomes.
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. subho@jimmy.harvard.edu
authors.forename: Subhajyoti
authors.initials: S
authors.lastname: De
authors.forename: Franziska
authors.initials: F
authors.lastname: Michor
mesh_terms: D045744:Cell Line, Tumor; D056915:DNA Copy Number Variations / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics; D042522:DNA Replication Timing / Q000235:genetics*; D044127:Epigenesis, Genetic; D015894:Genome, Human; D006801:Humans; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000235:genetics*
references.citation: J Biol Chem. 2003 Nov 7;278(45):43893-6
references.pmid: 13679382
references.citation: Nat Rev Cancer. 2004 Mar;4(3):177-83
references.pmid: 14993899
references.citation: Nature. 2011 Jun 29;474(7353):609-15
references.pmid: 21720365
references.citation: Nat Genet. 2009 Apr;41(4):393-5
references.pmid: 19287383
references.citation: Mutat Res. 1988 Jul-Aug;200(1-2):193-9
references.pmid: 3292906
references.citation: PLoS Genet. 2006 Apr;2(4):e48
references.pmid: 16604155
references.citation: Nat Struct Mol Biol. 2011 Jul 03;18(8):950-5
references.pmid: 21725294
references.citation: Nature. 2010 Feb 18;463(7283):899-905
references.pmid: 20164920
references.citation: Cell Mol Life Sci. 2010 Jan;67(1):43-62
references.pmid: 19727556
references.citation: Mol Cell Biol. 2005 Aug;25(16):7158-69
references.pmid: 16055725
references.citation: Hum Genet. 1997 Oct;100(5-6):525-35
references.pmid: 9341866
references.citation: Trends Genet. 2011 Feb;27(2):63-71
references.pmid: 21144612
references.citation: Cell Cycle. 2005 Jan;4(1):172-6
references.pmid: 15611667
references.citation: Science. 2009 Oct 9;326(5950):289-93
references.pmid: 19815776
references.citation: Science. 2005 Sep 2;309(5740):1581-4
references.pmid: 16141077
references.citation: Annu Rev Genomics Hum Genet. 2009;10:451-81
references.pmid: 19715442
references.citation: PLoS Genet. 2009 Jan;5(1):e1000327
references.pmid: 19180184
references.citation: Nat Rev Mol Cell Biol. 2009 Apr;10(4):243-54
references.pmid: 19277046
references.citation: Nat Rev Genet. 2010 Oct;11(10):673-84
references.pmid: 20811343
references.citation: Genome Res. 2010 Jun;20(6):761-70
references.pmid: 20430782
references.citation: Hum Mol Genet. 2002 Jan 1;11(1):13-21
references.pmid: 11772995
references.citation: Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):139-44
references.pmid: 19966280
references.citation: Cell. 2004 Sep 17;118(6):699-713
references.pmid: 15369670
references.citation: Nucleic Acids Res. 2010 Jul;38(12):3975-83
references.pmid: 20215435
references.citation: Nature. 2008 Oct 23;455(7216):1061-8
references.pmid: 18772890
references.citation: Brief Bioinform. 2010 Sep;11(5):484-98
references.pmid: 20519329
references.citation: Cell. 2006 Jun 30;125(7):1233-5
references.pmid: 16814710
references.citation: Annu Rev Biochem. 2002;71:333-74
references.pmid: 12045100
references.citation: Nat Rev Genet. 2009 Aug;10(8):551-64
references.pmid: 19597530
references.citation: Nat Rev Genet. 2010 Oct;11(10):685-96
references.pmid: 20847746