Comprehensive genomic characterization defines human glioblastoma genes and core pathways.
Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas (TCGA) pilot project aims to assess the value of large-scale multi-dimensional analysis of these molecular characteristics in human cancer and to provide the data rapidly to the research community. Here we report the interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas--the most common type of adult brain cancer--and nucleotide sequence aberrations in 91 of the 206 glioblastomas. This analysis provides new insights into the roles of ERBB2, NF1 and TP53, uncovers frequent mutations of the phosphatidylinositol-3-OH kinase regulatory subunit gene PIK3R1, and provides a network view of the pathways altered in the development of glioblastoma. Furthermore, integration of mutation, DNA methylation and clinical treatment data reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated glioblastomas, an observation with potential clinical implications. Together, these findings establish the feasibility and power of TCGA, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer.
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000235:genetics*; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D018773:Genes, erbB-1 / Q000235:genetics; D015894:Genome, Human / Q000235:genetics; D023281:Genomics; D005909:Glioblastoma / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D025542:Neurofibromin 1 / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D017434:Protein Structure, Tertiary; D012189:Retrospective Studies; D015398:Signal Transduction / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
D025542:Neurofibromin 1; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D019869:Phosphatidylinositol 3-Kinases; D045643:DNA Repair Enzymes
Int J Cancer. 2008 Jul 15;123(2):258-263
18464258
Cancer Res. 2004 Sep 15;64(18):6503-10
15374961
N Engl J Med. 1997 Jun 12;336(24):1713-20
9180088
PLoS One. 2008 Sep 11;3(9):e3179
18784837
Nat Rev Cancer. 2005 Dec;5(12):921-9
16341083
Proc Natl Acad Sci U S A. 1990 Jun;87(11):4207-11
1693434
Clin Cancer Res. 2007 Apr 1;13(7):2038-45
17404084
Hum Mutat. 2000;15(6):541-55
10862084
Cancer Res. 2006 Dec 1;66(23):11502-13
17114236
Nature. 2006 Jan 19;439(7074):358-62
16273091
Science. 2007 Oct 12;318(5848):287-90
17872411
Cancer Cell. 2006 May;9(5):391-403
16697959
Prog Nucleic Acid Res Mol Biol. 1995;51:167-223
7659775
N Engl J Med. 2000 Nov 9;343(19):1350-4
11070098
Cancer Biol Ther. 2003 May-Jun;2(3):242-7
12878856
Science. 2007 Dec 14;318(5857):1744-8
18079394
N Engl J Med. 2005 Mar 10;352(10):997-1003
15758010
J Clin Oncol. 2008 Jun 20;26(18):3015-24
18565887
Proc Natl Acad Sci U S A. 2005 Apr 19;102(16):5814-9
15827123
Brain Pathol. 2003 Jan;13(1):52-61
12580545
Brain Pathol. 2004 Oct;14(4):372-7
15605984
Cancer Res. 2008 May 1;68(9):3286-94
18451155
Br J Cancer. 2004 Jul 19;91(2):355-8
15188009
Science. 2004 Apr 23;304(5670):554
15016963
Genes Dev. 2007 Nov 1;21(21):2683-710
17974913
Mol Cancer Res. 2006 Oct;4(10):709-14
17050665
PLoS Med. 2006 Dec;3(12):e485
17177598
Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1475-9
16432179
DNA Repair (Amst). 2007 Aug 1;6(8):1079-99
17485253
DNA Repair (Amst). 2004 Nov 2;3(11):1389-407
15380096
Nat Genet. 2000 Sep;26(1):109-13
10973261
Cancer Res. 2003 Apr 1;63(7):1602-7
12670911
Proc Natl Acad Sci U S A. 2008 Apr 1;105(13):5213-8
18362333
Anticancer Res. 1995 Nov-Dec;15(6B):2495-9
8669813
Cancer Res. 2006 Apr 15;66(8):3987-91
16618716
Nature. 2004 Sep 30;431(7008):525-6
15457249
Proc Natl Acad Sci U S A. 1992 May 15;89(10):4309-13
1584765
Anticancer Agents Med Chem. 2008 May;8(4):368-80
18473722
Cancer Cell. 2008 Apr;13(4):355-64
18394558
Cancer Cell. 2005 Aug;8(2):119-30
16098465
Breast Cancer Res Treat. 2008 Nov;112(2):217-27
18074223
Am J Hum Genet. 2000 Mar;66(3):790-818
10712197
Hum Genet. 1997 Jan;99(1):88-92
9003501
Science. 2007 Sep 14;317(5844):1500
17872428
Cancer Cell. 2006 Mar;9(3):157-73
16530701
Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):20007-12
18077431
Cancer Cell. 2006 Apr;9(4):287-300
16616334
J Neurosurg. 2003 Mar;98(3):591-8
12650433
Cancer Res. 2001 Oct 15;61(20):7426-9
11606375
Cell Cycle. 2006 Apr;5(7):675-7
16627990