title: THetA: inferring intra-tumor heterogeneity from high-throughput DNA sequencing data.
abstract: Tumor samples are typically heterogeneous, containing admixture by normal, non-cancerous cells and one or more subpopulations of cancerous cells. Whole-genome sequencing of a tumor sample yields reads from this mixture, but does not directly reveal the cell of origin for each read. We introduce THetA (Tumor Heterogeneity Analysis), an algorithm that infers the most likely collection of genomes and their proportions in a sample, for the case where copy number aberrations distinguish subpopulations. THetA successfully estimates normal admixture and recovers clonal and subclonal copy number aberrations in real and simulated sequencing data. THetA is available at http://compbio.cs.brown.edu/software/.
authors.forename: Layla
authors.initials: L
authors.lastname: Oesper
authors.forename: Ahmad
authors.initials: A
authors.lastname: Mahmoody
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Raphael
mesh_terms: D000465:Algorithms; D001943:Breast Neoplasms / Q000235:genetics*; D003198:Computer Simulation; D005260:Female; D018740:Genetic Heterogeneity; D015894:Genome, Human / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D016013:Likelihood Functions; D012984:Software; D013223:Statistics as Topic
references.citation: Nat Methods. 2009 Sep;6(9):677-81
references.pmid: 19668202
references.citation: Bioinformatics. 2004 Aug 4;20 Suppl 1:i265-73
references.pmid: 15262808
references.citation: Cancer Res. 1996 Dec 15;56(24):5605-9
references.pmid: 8971163
references.citation: Genes Chromosomes Cancer. 1997 Jul;19(3):185-91
references.pmid: 9219000
references.citation: Nucleic Acids Res. 2004 Jan 1;32(Database issue):D493-6
references.pmid: 14681465
references.citation: N Engl J Med. 2013 May 30;368(22):2059-74
references.pmid: 23634996
references.citation: Nature. 2011 Apr 7;472(7341):90-4
references.pmid: 21399628
references.citation: Cell. 2012 Mar 2;148(5):886-95
references.pmid: 22385958
references.citation: Sci Transl Med. 2012 Oct 24;4(157):157ra143
references.pmid: 23100629
references.citation: Science. 2012 Apr 20;336(6079):304-5
references.pmid: 22517848
references.citation: Genome Res. 2012 Feb;22(2):346-61
references.pmid: 21994251
references.citation: Cancer Lett. 2013 Nov 1;340(2):212-9
references.pmid: 23353056
references.citation: Nat Methods. 2009 Jan;6(1):99-103
references.pmid: 19043412
references.citation: Br J Cancer. 1999 Dec;81(8):1410-8
references.pmid: 10604741
references.citation: Genes Chromosomes Cancer. 2008 Aug;47(8):680-96
references.pmid: 18398821
references.citation: Nat Biotechnol. 2012 May;30(5):413-21
references.pmid: 22544022
references.citation: Proc Natl Acad Sci U S A. 2011 Nov 15;108(46):E1128-36
references.pmid: 22065754
references.citation: Proc Natl Acad Sci U S A. 2010 Sep 28;107(39):16910-5
references.pmid: 20837533
references.citation: Science. 2008 Nov 28;322(5906):1377-80
references.pmid: 19039135
references.citation: Genome Res. 2009 Feb;19(2):276-83
references.pmid: 19141597
references.citation: Cancer Res. 2005 Jan 1;65(1):66-75
references.pmid: 15665280
references.citation: Am J Hum Genet. 2008 Apr;82(4):903-15
references.pmid: 18355774
references.citation: N Engl J Med. 2012 Mar 8;366(10):883-892
references.pmid: 22397650
references.citation: PLoS Comput Biol. 2008 Apr 25;4(4):e1000051
references.pmid: 18404202
references.citation: Cancer Res. 2000 Jun 1;60(11):2836-9
references.pmid: 10850424
references.citation: Bioinformatics. 2003 Oct;19 Suppl 2:ii162-71
references.pmid: 14534186
references.citation: Genome Res. 2012 Nov;22(11):2250-61
references.pmid: 22745232
references.citation: Biostatistics. 2010 Jan;11(1):164-75
references.pmid: 19837654
references.citation: Genes Chromosomes Cancer. 1995 Jul;13(3):186-91
references.pmid: 7669738
references.citation: Genome Res. 2010 Jan;20(1):68-80
references.pmid: 19903760
references.citation: Bioinformatics. 2012 Sep 1;28(17):2265-6
references.pmid: 22743227
references.citation: Cell. 2012 Mar 2;148(5):873-85
references.pmid: 22385957
references.citation: Hereditas. 1997;126(3):261-8
references.pmid: 9350140
references.citation: Mutat Res. 2008 Sep-Oct;659(3):232-47
references.pmid: 18614394
references.citation: Nat Protoc. 2012 May 03;7(6):1024-41
references.pmid: 22555242
references.citation: Bioinformatics. 2012 Jan 1;28(1):40-7
references.pmid: 22039209
references.citation: BMC Genomics. 2011 May 11;12:230
references.pmid: 21569352
references.citation: Science. 1976 Oct 1;194(4260):23-8
references.pmid: 959840
references.citation: BMC Bioinformatics. 2012 Apr 19;13 Suppl 6:S10
references.pmid: 22537039
references.citation: Nature. 2012 Apr 04;486(7403):395-9
references.pmid: 22495314
references.citation: PLoS One. 2011 Jan 31;6(1):e16327
references.pmid: 21305028
references.citation: Genome Res. 2012 Mar;22(3):568-76
references.pmid: 22300766
references.citation: Nat Rev Genet. 2010 Oct;11(10):685-96
references.pmid: 20847746
references.citation: Genome Res. 2012 Feb;22(2):362-74
references.pmid: 22090379
references.citation: Am J Pathol. 1998 Mar;152(3):815-9
references.pmid: 9502423
references.citation: Cell. 2013 Mar 14;152(6):1226-36
references.pmid: 23498933
references.citation: Bioinformatics. 2010 Jun 15;26(12):i106-14
references.pmid: 20529894
references.citation: Hum Mol Genet. 2010 Oct 15;19(R2):R188-96
references.pmid: 20843826
references.citation: Cell. 2013 Feb 14;152(4):714-26
references.pmid: 23415222
references.citation: Cell. 2012 May 25;149(5):994-1007
references.pmid: 22608083
references.citation: Bioinformatics. 2009 Nov 1;25(21):2882-9
references.pmid: 19542156
references.citation: Bioinformatics. 2009 Jun 15;25(12):i222-30
references.pmid: 19477992
references.citation: Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):5546-51
references.pmid: 23503850
references.citation: Genome Biol. 2010;11(9):R92
references.pmid: 20858232
references.citation: Nature. 2012 Jan 18;481(7381):306-13
references.pmid: 22258609
references.citation: Nature. 2012 Jan 11;481(7382):506-10
references.pmid: 22237025
references.citation: Bioinformatics. 2012 Aug 15;28(16):2097-105
references.pmid: 22668792