Functional copy-number alterations in cancer.
Understanding the molecular basis of cancer requires characterization of its genetic defects. DNA microarray technologies can provide detailed raw data about chromosomal aberrations in tumor samples. Computational analysis is needed (1) to deduce from raw array data actual amplification or deletion events for chromosomal fragments and (2) to distinguish causal chromosomal alterations from functionally neutral ones. We present a comprehensive computational approach, RAE, designed to robustly map chromosomal alterations in tumor samples and assess their functional importance in cancer. To demonstrate the methodology, we experimentally profile copy number changes in a clinically aggressive subtype of soft-tissue sarcoma, pleomorphic liposarcoma, and computationally derive a portrait of candidate oncogenic alterations and their target genes. Many affected genes are known to be involved in sarcomagenesis; others are novel, including mediators of adipocyte differentiation, and may include valuable therapeutic targets. Taken together, we present a statistically robust methodology applicable to high-resolution genomic data to assess the extent and function of copy-number alterations in cancer.
Taylor
Barry S
BS
Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America. copy-number@cbio.mskcc.org
Barretina
Jordi
J
Socci
Nicholas D
ND
Decarolis
Penelope
P
Ladanyi
Marc
M
Meyerson
Matthew
M
Singer
Samuel
S
Sander
Chris
C
D002869:Chromosome Aberrations; D016000:Cluster Analysis; D005784:Gene Amplification; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D023281:Genomics / Q000379:methods*; D006801:Humans; D008957:Models, Genetic; D015233:Models, Statistical; D009369:Neoplasms / Q000235:genetics*; D010641:Phenotype; D016012:Poisson Distribution; D020641:Polymorphism, Single Nucleotide
Science. 1987 Jan 9;235(4785):177-82
3798106
Science. 2005 Oct 14;310(5746):321-4
16224025
Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):9067-72
15199222
Cancer Res. 1995 Oct 15;55(20):4670-5
7553647
Br J Cancer. 2004 Jul 19;91(2):355-8
15188009
Ann Surg. 2006 Sep;244(3):381-91
16926564
Annu Rev Genomics Hum Genet. 2002;3:199-242
12142364
Nature. 2007 Oct 18;449(7164):851-61
17943122
Nature. 2007 Dec 6;450(7171):893-8
17982442
N Engl J Med. 2004 May 20;350(21):2129-39
15118073
Genome Res. 2006 Aug;16(8):949-61
16809666
Cancer Res. 2007 Jul 15;67(14):6626-36
17638873
Nat Rev Cancer. 2003 Sep;3(9):685-94
12951587
Nature. 2007 Mar 8;446(7132):153-8
17344846
PLoS Genet. 2007 Aug;3(8):e143
17722985
Nat Biotechnol. 2000 Sep;18(9):1001-5
10973224
Science. 2008 Mar 7;319(5868):1395-8
18239090
Nat Rev Cancer. 2004 Mar;4(3):177-83
14993899
Int J Cancer. 2002 May 1;99(1):68-73
11948494
Hum Pathol. 2005 Oct;36(10):1037-48
16226102
Cancer Res. 2002 Jun 1;62(11):2993-8
12036902
Nat Genet. 2003 Aug;34(4):369-76
12923544
Science. 2006 Oct 13;314(5797):268-74
16959974
Nat Rev Mol Cell Biol. 2006 Dec;7(12):885-96
17139329
Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13306-11
15329413
Bioinformatics. 2007 Nov 15;23(22):3091-2
17599934
Science. 2004 Jul 23;305(5683):525-8
15273396
J Biol Chem. 2002 May 10;277(19):16906-12
11884404
DNA Seq. 2006 Jun;17(3):242-6
17286053
Bioinformatics. 2007 Jul 1;23(13):i450-8
17646330
Biochem Biophys Res Commun. 2005 May 6;330(2):505-10
15796911
Science. 2007 Sep 14;317(5844):1500; author reply 1500
17872427
Nat Genet. 2005 Jun;37 Suppl:S11-7
15920524
Am J Med Genet. 2000 Aug 28;93(5):388-92
10951462
Bioinformatics. 2005 Oct 1;21(19):3763-70
16081473
Science. 2004 Jun 4;304(5676):1497-500
15118125
Cancer Cell. 2007 Apr;11(4):361-74
17418412
Nat Rev Genet. 2007 Nov;8(11):869-83
17943194
Am J Hum Genet. 2008 Mar;82(3):685-95
18304495
Biostatistics. 2004 Oct;5(4):557-72
15475419
Proc Natl Acad Sci U S A. 2005 Jul 5;102(27):9625-30
15983384
Science. 2004 Apr 23;304(5670):581-4
15105499
Science. 2007 Sep 14;317(5844):1500
17872429
Bioinformatics. 2005 Nov 15;21(22):4084-91
16159913
Genome Res. 2006 Sep;16(9):1149-58
16899652
Genome Biol. 2004;5(10):242
15461806
Nat Genet. 2004 Sep;36(9):949-51
15286789
Cancer. 1995 Jan 1;75(1 Suppl):211-44
8000998
Science. 2007 Sep 14;317(5844):1500
17872428
Science. 2007 May 18;316(5827):1039-43
17463250
Semin Cancer Biol. 2002 Oct;12(5):373-9
12191636
Blood. 1997 Dec 15;90(12):4699-704
9389684
Cancer Cell. 2006 Apr;9(4):313-25
16616336
JAMA. 1997 Oct 15;278(15):1262-7
9333268
N Engl J Med. 2001 Apr 5;344(14):1031-7
11287972
Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):20007-12
18077431
Science. 2007 Nov 16;318(5853):1108-13
17932254
Nature. 2006 Nov 23;444(7118):444-54
17122850
Oncogene. 2007 May 24;26(24):3473-81
17146434