Microarray analyses reveal strong influence of DNA copy number alterations on the transcriptional patterns in pancreatic cancer: implications for the interpretation of genomic amplifications

Abstract

DNA copy number alterations are believed to play a major role in the development and progression of human neoplasms. Although most of these genomic imbalances have been associated with dysregulation of individual genes, their large-scale transcriptional consequences remain unclear. Pancreatic carcinomas frequently display gene copy number variation of entire chromosomes as well as of chromosomal subregions. These changes range from homozygous deletions to high-level amplifications and are believed to constitute key genetic alterations in the cellular transformation of this tumor type. To investigate the transcriptional consequences of the most drastic genomic changes, that is, genomic amplifications, and to analyse the genome-wide transcriptional effects of DNA copy number changes, we performed expression profiling of 29 pancreatic carcinoma cell lines and compared the results with matching genomic profiling data. We show that a strong association between DNA copy numbers and mRNA expression levels is present in pancreatic cancer, and demonstrate that as much as 60% of the genes within highly amplified genomic regions display associated overexpression. Consequently, we identified 67 recurrently overexpressed genes located in seven precisely mapped commonly amplified regions. The presented findings indicate that more than one putative target gene may be of importance in most pancreatic cancer amplicons.

DNA amplification is a ubiquitous mechanism of oncogene activation in lung and other cancers

“…This falls within observations of previous studies that reported 19.3-62% of amplified genes being overexpressed (Hyman et al, 2002;Pollack et al, 2002;Wolf et al, 2004;Heidenblad et al, 2005). Nevertheless, since this is the first study to integrate high-resolution copy number and gene expression profiles in lung cancer on a whole-genome scale, future analysis will be needed to confirm the functional impact of the genes in each amplicon.…”

Correlation between genomic DNA copy number alterations and transcriptional expression in hepatitis B virus‐associated hepatocellular carcinoma

“…The previous studies revealed that the DNA copy number alterations can lead directly to global deregulation of gene expression in breast tumors [14,15], pancreatic cancers [16,17], an immortalized prostate epithelial cell line [18], and artificial chromosome trisomies [19], which could contribute to the development or progression of cancers. In contrast, only $4% of genes within these amplified regions were found to be highly expressed in metastatic colon tumors [20].…”

Frequent genomic copy number gain and overexpression of GATA-6 in pancreatic carcinoma

“…[3][4][5][6][7] For example, novel candidate oncogenes include SMURF1 on 7q21, FGFR1 on 8p12, BIRC2 and BIRC3 on 11q22 and PAK4 on 19q13 while novel candidate tumor suppressor genes include TUSC3 on 8p22 and FEZ1 on 8p23. [4][5][6][7][8] The objective of this study was to identify novel targets of genetic alteration that contribute to pancreatic cancer development or progression. Towards this goal, we used the high resolution method Representational Oligonucleotide Microarray Analysis (ROMA) to identify novel copy number changes of significance in pancreatic cancer.…”