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.
Highlights
Gastric cancer is one of the most common malignancies and the second most common cause of cancer related death worldwide [1]
This study provides insight into DNA copy number variations and their contribution to altered gene expression profiles during human gastric cancer development
Most gastric cancer patients are identified at the advanced stage, which leads to the dismal prognosis
Summary
Gastric cancer is one of the most common malignancies and the second most common cause of cancer related death worldwide [1]. The major type of gastric cancer is adenocarcinoma, which can be further categorized into intestinal type and diffuse type [2]. Surgical treatment is the only therapeutic modality that has a potentially curative effect to gastric cancer. The prognosis of gastric cancer patients depends heavily on the clinical and pathological stage of the disease at diagnosis. Most gastric cancer patients are identified at the advanced stage, which leads to the dismal prognosis. 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
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