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Integrative genomics reveals mechanisms of copy number alterations responsible for transcriptional deregulation in colorectal cancer.


ABSTRACT: 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.

SUBMITTER: Camps J 

PROVIDER: S-EPMC4721599 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Integrative genomics reveals mechanisms of copy number alterations responsible for transcriptional deregulation in colorectal cancer.

Camps Jordi J   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  

Genes, chromosomes & cancer 20091101 11


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) i  ...[more]

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