Integrative genomics reveals mechanisms of copy number alterations responsible for transcriptional deregulation in colorectal cancer.
To evaluate the mechanisms and consequences of chromosomal aberrations in colorectal cancer (CRC), we used a combination of spectral karyotyping, array comparative genomic hybridization (aCGH), and array-based global gene expression profiling on 31 primary carcinomas and 15 established cell lines. Importantly, aCGH showed that the genomic profiles of primary tumors are recapitulated in the cell lines. We revealed a preponderance of chromosome breakpoints at sites of copy number variants (CNVs) in the CRC cell lines, a novel mechanism of DNA breakage in cancer. The integration of gene expression and aCGH led to the identification of 157 genes localized within high-level copy number changes whose transcriptional deregulation was significantly affected across all of the samples, thereby suggesting that these genes play a functional role in CRC. Genomic amplification at 8q24 was the most recurrent event and led to the overexpression of MYC and FAM84B. Copy number dependent gene expression resulted in deregulation of known cancer genes such as APC, FGFR2, and ERBB2. The identification of only 36 genes whose localization near a breakpoint could account for their observed deregulated expression demonstrates that the major mechanism for transcriptional deregulation in CRC is genomic copy number changes resulting from chromosomal aberrations.
Camps
Jordi
J
Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Nguyen
Quang Tri
QT
Padilla-Nash
Hesed M
HM
Knutsen
Turid
T
McNeil
Nicole E
NE
Wangsa
Danny
D
Hummon
Amanda B
AB
Grade
Marian
M
Ried
Thomas
T
Difilippantonio
Michael J
MJ
D045744:Cell Line, Tumor; D056905:Chromosome Breakpoints; D002898:Chromosomes, Human, Pair 8; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D055028:Comparative Genomic Hybridization / Q000379:methods; D056915:DNA Copy Number Variations; D017353:Gene Deletion; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism; D032681:Spectral Karyotyping / Q000379:methods; D014158:Transcription, Genetic
C453442:FAM89B protein, human; D009363:Neoplasm Proteins; D016271:Proto-Oncogene Proteins c-myc; D011991:Receptors, Virus
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