title: Calling amplified haplotypes in next generation tumor sequence data.
abstract: During tumor initiation and progression, cancer cells acquire a selective advantage, allowing them to outcompete their normal counterparts. Identification of the genetic changes that underlie these tumor acquired traits can provide deeper insights into the biology of tumorigenesis. Regions of copy number alterations and germline DNA variants are some of the elements subject to selection during tumor evolution. Integrated examination of inherited variation and somatic alterations holds the potential to reveal specific nucleotide alleles that a tumor "prefers" to have amplified. Next-generation sequencing of tumor and matched normal tissues provides a high-resolution platform to identify and analyze such somatic amplicons. Within an amplicon, examination of informative (e.g., heterozygous) sites deviating from a 1:1 ratio may suggest selection of that allele. A naive approach examines the reads for each heterozygous site in isolation; however, this ignores available valuable linkage information across sites. We, therefore, present a novel hidden Markov model-based method-Haplotype Amplification in Tumor Sequences (HATS)-that analyzes tumor and normal sequence data, along with training data for phasing purposes, to infer amplified alleles and haplotypes in regions of copy number gain. Our method is designed to handle rare variants and biases in read data. We assess the performance of HATS using simulated amplified regions generated from varying copy number and coverage levels, followed by amplicons in real data. We demonstrate that HATS infers the amplified alleles more accurately than does the naive approach, especially at low to intermediate coverage levels and in cases (including high coverage) possessing stromal contamination or allelic bias.
authors.affiliation: Department of Biomedical Informatics, Columbia University, New York, New York 10032, USA.
authors.forename: Ninad
authors.initials: N
authors.lastname: Dewal
authors.forename: Yang
authors.initials: Y
authors.lastname: Hu
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Freedman
authors.forename: Thomas
authors.initials: T
authors.lastname: Laframboise
authors.forename: Itsik
authors.initials: I
authors.lastname: Pe'er
mesh_terms: D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D005784:Gene Amplification; D006239:Haplotypes; D006801:Humans; D008957:Models, Genetic; D009369:Neoplasms / Q000235:genetics*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
references.citation: Nat Methods. 2009 Jul;6(7):473-4
references.pmid: 19483690
references.citation: Nature. 2011 Jun 29;474(7353):609-15
references.pmid: 21720365
references.citation: Bioinformatics. 2010 Feb 15;26(4):518-28
references.pmid: 20031965
references.citation: Am J Hum Genet. 2006 Mar;78(3):437-50
references.pmid: 16465620
references.citation: Proc Natl Acad Sci U S A. 2006 Sep 19;103(38):14068-73
references.pmid: 16945910
references.citation: Bioinformatics. 2009 Jul 15;25(14):1754-60
references.pmid: 19451168
references.citation: Genome Res. 2009 Sep;19(9):1527-41
references.pmid: 19546169
references.citation: Nat Genet. 2007 Aug;39(8):989-94
references.pmid: 17618283
references.citation: BMC Bioinformatics. 2009 Mar 06;10:80
references.pmid: 19267900
references.citation: Nature. 2008 Apr 3;452(7187):633-7
references.pmid: 18385738
references.citation: Nat Methods. 2009 Sep;6(9):677-81
references.pmid: 19668202
references.citation: Am J Hum Genet. 2007 Nov;81(5):1084-97
references.pmid: 17924348
references.citation: Science. 1998 May 15;280(5366):1077-82
references.pmid: 9582121
references.citation: Nat Methods. 2009 Jan;6(1):99-103
references.pmid: 19043412
references.citation: Nat Genet. 2005 Jul;37(7):727-32
references.pmid: 15895083
references.citation: Genome Biol. 2009;10(3):R25
references.pmid: 19261174
references.citation: Nature. 2010 Oct 28;467(7319):1061-73
references.pmid: 20981092
references.citation: Genome Res. 2009 Jul;19(7):1270-8
references.pmid: 19447966
references.citation: Hum Mol Genet. 2009 Jun 15;18(12):2297-304
references.pmid: 19304784
references.citation: PLoS Genet. 2009 Mar;5(3):e1000411
references.pmid: 19282976
references.citation: PLoS Comput Biol. 2005 Nov;1(6):e65
references.pmid: 16322765
references.citation: Biostatistics. 2008 Apr;9(2):321-32
references.pmid: 17728317
references.citation: Genes Chromosomes Cancer. 1997 Dec;20(4):399-407
references.pmid: 9408757
references.citation: J Clin Oncol. 2010 Sep 20;28(27):4255-67
references.pmid: 20585100
references.citation: Cancer Res. 2003 Aug 15;63(16):4849-53
references.pmid: 12941805
references.citation: Nature. 1983 Oct 27-Nov 2;305(5937):779-84
references.pmid: 6633649
references.citation: Microbiol Mol Biol Rev. 1999 Jun;63(2):349-404
references.pmid: 10357855
references.citation: Nat Genet. 2003 Aug;34(4):403-12
references.pmid: 12881723
references.citation: Biostatistics. 2007 Apr;8(2):323-36
references.pmid: 16787995
references.citation: PLoS One. 2010 Feb 19;5(2):e9317
references.pmid: 20174472
references.citation: Am J Hum Genet. 2001 Apr;68(4):978-89
references.pmid: 11254454
references.citation: Carcinogenesis. 2010 Jan;31(1):111-20
references.pmid: 19906782
references.citation: Genes Chromosomes Cancer. 1998 Feb;21(2):172-5
references.pmid: 9491330
references.citation: Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9362-7
references.pmid: 19474294
references.citation: Bioinformatics. 2004 May 22;20(8):1233-40
references.pmid: 14871870
references.citation: Anal Biochem. 2002 Feb 1;301(1):82-90
references.pmid: 11811970
references.citation: Genome Res. 2009 Sep;19(9):1586-92
references.pmid: 19657104
references.citation: BMC Bioinformatics. 2006 Dec 22;7:542
references.pmid: 17187677
references.citation: Genes Chromosomes Cancer. 1999 Jun;25(2):82-90
references.pmid: 10337990
references.citation: Nature. 2005 Oct 27;437(7063):1299-320
references.pmid: 16255080
references.citation: Nat Genet. 2008 May;40(5):616-22
references.pmid: 18385676
references.citation: Prostate. 2007 May 15;67(7):692-700
references.pmid: 17342750
references.citation: Nat Genet. 2009 Apr;41(4):450-4
references.pmid: 19287385
references.citation: Am J Hum Genet. 2006 Apr;78(4):629-44
references.pmid: 16532393
references.citation: Genes Chromosomes Cancer. 1995 Dec;14(4):267-76
references.pmid: 8605115
references.citation: Genome Res. 2006 Dec;16(12):1575-84
references.pmid: 17122084
references.citation: Bioinformatics. 2008 Mar 1;24(5):713-4
references.pmid: 18227114
references.citation: Proc Natl Acad Sci U S A. 2006 Aug 22;103(34):12819-24
references.pmid: 16908833
references.citation: Science. 1992 Oct 30;258(5083):818-21
references.pmid: 1359641
references.citation: Genome Biol. 2010;11(10):R106
references.pmid: 20979621
references.citation: Nature. 1995 Dec 21-28;378(6559):789-92
references.pmid: 8524414
references.citation: Cancer Res. 2005 Jul 15;65(14):6071-9
references.pmid: 16024607
references.citation: PLoS Genet. 2010 Sep 02;6(9):e1001086
references.pmid: 20824129
references.citation: Bioinformatics. 2010 Jan 1;26(1):139-40
references.pmid: 19910308
references.citation: Hum Mol Genet. 2008 Oct 15;17(R2):R109-15
references.pmid: 18852198
references.citation: Science. 1976 Oct 1;194(4260):23-8
references.pmid: 959840
references.citation: Nature. 2008 Nov 6;456(7218):53-9
references.pmid: 18987734
references.citation: Nat Genet. 2009 May;41(5):585-90
references.pmid: 19330027
references.citation: J Comput Biol. 2005 Dec;12(10):1243-60
references.pmid: 16379532
references.citation: Cancer Res. 1996 Jul 1;56(13):3091-102
references.pmid: 8674067
references.citation: Oncology (Williston Park). 2010 Jun;24(7):629-37
references.pmid: 20669800
references.citation: Surg Oncol Clin N Am. 2009 Oct;18(4):663-8
references.pmid: 19793573
references.citation: Genome Res. 2008 Nov;18(11):1851-8
references.pmid: 18714091
references.citation: Nat Genet. 2009 Apr;41(4):455-9
references.pmid: 19287384
references.citation: Cancer Res. 2005 Jul 1;65(13):5561-70
references.pmid: 15994928
references.citation: Hum Mol Genet. 2004 Jul 1;13(13):1303-13
references.pmid: 15138198
references.citation: Nature. 2008 Apr 3;452(7187):638-642
references.pmid: 18385739
references.citation: Nat Rev Genet. 2008 May;9(5):356-69
references.pmid: 18398418
references.citation: Nature. 2008 Oct 23;455(7216):1061-8
references.pmid: 18772890
references.citation: Hum Mol Genet. 2010 Jan 1;19(1):122-34
references.pmid: 19825846
references.citation: Nat Genet. 2004 Mar;36(3):299-303
references.pmid: 14981516
references.citation: Brief Bioinform. 2010 Jan;11(1):3-14
references.pmid: 20053733
references.citation: Science. 2007 Oct 19;318(5849):420-6
references.pmid: 17901297
references.citation: Genome Res. 2010 Nov;20(11):1613-22
references.pmid: 20805290
references.citation: Annu Rev Public Health. 2010;31:9-20 4 p following 20
references.pmid: 20235850
references.citation: Cancer Metastasis Rev. 2009 Dec;28(3-4):269-80
references.pmid: 20016998
references.citation: Science. 1994 Oct 7;266(5182):66-71
references.pmid: 7545954
references.citation: Nat Genet. 2009 Apr;41(4):446-9
references.pmid: 19287382
references.citation: Bioinformatics. 2009 Aug 15;25(16):2078-9
references.pmid: 19505943
references.citation: Genet Epidemiol. 2007 Dec;31(8):937-48
references.pmid: 17630649
references.citation: Nat Genet. 2009 Oct;41(10):1061-7
references.pmid: 19718026
references.citation: Int J Cancer. 2006 Jan 15;118(2):505-8
references.pmid: 16049965
references.citation: Oncogene. 2007 Jun 14;26(28):4171-8
references.pmid: 17311004
references.citation: Science. 1990 Dec 21;250(4988):1684-9
references.pmid: 2270482
references.citation: Cancer Epidemiol Biomarkers Prev. 2008 Mar;17(3):702-5
references.pmid: 18349290
references.citation: Anal Biochem. 1996 Nov 1;242(1):84-9
references.pmid: 8923969
references.citation: Nat Genet. 2008 Oct;40(10):1253-60
references.pmid: 18776909
references.citation: Nat Genet. 2006 Jun;38(6):652-8
references.pmid: 16682969
references.citation: Nat Genet. 2010 Jun;42(6):504-7
references.pmid: 20453838
references.citation: Nat Methods. 2009 Aug;6(8):613-8
references.pmid: 19620972