Integration of DNA Copy Number Alterations and Transcriptional Expression Analysis in Human Gastric Cancer

Abstract

BackgroundGenomic instability with frequent DNA copy number alterations is one of the key hallmarks of carcinogenesis. The chromosomal regions with frequent DNA copy number gain and loss in human gastric cancer are still poorly defined. It remains unknown how the DNA copy number variations contributes to the changes of gene expression profiles, especially on the global level.Principal FindingsWe analyzed DNA copy number alterations in 64 human gastric cancer samples and 8 gastric cancer cell lines using bacterial artificial chromosome (BAC) arrays based comparative genomic hybridization (aCGH). Statistical analysis was applied to correlate previously published gene expression data obtained from cDNA microarrays with corresponding DNA copy number variation data to identify candidate oncogenes and tumor suppressor genes. We found that gastric cancer samples showed recurrent DNA copy number variations, including gains at 5p, 8q, 20p, 20q, and losses at 4q, 9p, 18q, 21q. The most frequent regions of amplification were 20q12 (7/72), 20q12–20q13.1 (12/72), 20q13.1–20q13.2 (11/72) and 20q13.2–20q13.3 (6/72). The most frequent deleted region was 9p21 (8/72). Correlating gene expression array data with aCGH identified 321 candidate oncogenes, which were overexpressed and showed frequent DNA copy number gains; and 12 candidate tumor suppressor genes which were down-regulated and showed frequent DNA copy number losses in human gastric cancers. Three networks of significantly expressed genes in gastric cancer samples were identified by ingenuity pathway analysis.ConclusionsThis study provides insight into DNA copy number variations and their contribution to altered gene expression profiles during human gastric cancer development. It provides novel candidate driver oncogenes or tumor suppressor genes for human gastric cancer, useful pathway maps for the future understanding of the molecular pathogenesis of this malignancy, and the construction of new therapeutic targets.

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“…Recently, some miRNAs were demonstrated to reduce AEG-1 expression. For instance, miR-375 could target AEG-1 to stimulate G1 arrest and apoptosis, and inhibit cell migration and invasion in head and neck cancer (Hui et al, 2011), and HCC (Fan et al, 2012); miR-136 triggered apoptosis partially by targeting AEG-1 in human glioma (Yang et al, 2012); and miR-26a was found to negatively regulate AEG-1 to enhance apoptosis in breast cancer (Zhang et al, 2011). Previous study reported that AEG-1 expression displayed increasing trend from normal liver tissue to hepatitis B and HBV-related HCC samples (Gong et al, 2012), which suggests that HBV may be involved in augmenting AEG-1 expression.…”

ZNF313 is a novel cell cycle activator with an E3 ligase activity inhibiting cellular senescence by destabilizing p21WAF1

“…3,6,7 A recent study also revealed that 20q12-q13.3 is the most frequently amplified region in gastric cancer. 42 Several genes located at this locus, such as AIB1 and BCAS1, have been shown to be involved in growth and aggressiveness of human cancers. 43,44 However, biological functions of putative tumor-promoting genes in this region have not been well characterized.…”

Runx3 at the interface of immunity, inflammation and cancer

“…However, the finding that in all GC samples there were at least two RUNX3-specific FISH signals per cell [19] indicates that there is no loss of RUNX3 in GC but rather amplification of regions encompassing the chromosome 1 centromere [19]. Furthermore, two recent high-resolution comparative genomic hybridization (CGH) studies of GC biopsies one involving 193 patients and the other 64 patients, revealed that the chromosome 1p36 region, which harbors RUNX3, was not frequently deleted in GC [73,74]. The genomic regions that were recurrently deleted in GC harbored various known TSGs, while the frequently amplified ones housed known oncogenes [73] (Table 4).…”