Abstract
BackgroundCancer-related genes show racial differences. Therefore, identification and characterization of DNA copy number alteration regions in different racial groups helps to dissect the mechanism of tumorigenesis.MethodsArray-comparative genomic hybridization (array-CGH) was analyzed for DNA copy number profile in 40 Asian and 20 Caucasian lung cancer patients. Three methods including MetaCore analysis for disease and pathway correlations, concordance analysis between array-CGH database and the expression array database, and literature search for copy number variation genes were performed to select novel lung cancer candidate genes. Four candidate oncogenes were validated for DNA copy number and mRNA and protein expression by quantitative polymerase chain reaction (qPCR), chromogenic in situ hybridization (CISH), reverse transcriptase-qPCR (RT-qPCR), and immunohistochemistry (IHC) in more patients.ResultsWe identified 20 chromosomal imbalance regions harboring 459 genes for Caucasian and 17 regions containing 476 genes for Asian lung cancer patients. Seven common chromosomal imbalance regions harboring 117 genes, included gain on 3p13-14, 6p22.1, 9q21.13, 13q14.1, and 17p13.3; and loss on 3p22.2-22.3 and 13q13.3 were found both in Asian and Caucasian patients. Gene validation for four genes including ARHGAP19 (10q24.1) functioning in Rho activity control, FRAT2 (10q24.1) involved in Wnt signaling, PAFAH1B1 (17p13.3) functioning in motility control, and ZNF322A (6p22.1) involved in MAPK signaling was performed using qPCR and RT-qPCR. Mean gene dosage and mRNA expression level of the four candidate genes in tumor tissues were significantly higher than the corresponding normal tissues (P<0.001~P=0.06). In addition, CISH analysis of patients indicated that copy number amplification indeed occurred for ARHGAP19 and ZNF322A genes in lung cancer patients. IHC analysis of paraffin blocks from Asian Caucasian patients demonstrated that the frequency of PAFAH1B1 protein overexpression was 68% in Asian and 70% in Caucasian.ConclusionsOur study provides an invaluable database revealing common and differential imbalance regions at specific chromosomes among Asian and Caucasian lung cancer patients. Four validation methods confirmed our database, which would help in further studies on the mechanism of lung tumorigenesis.
Highlights
Our array-CGH data has been submitted to Gene Expression Omnibus (GEO) database of NCBI with accession number GSE21276
chromogenic in situ hybridization (CISH) analysis of patients indicated that copy number amplification occurred for ARHGAP19 and ZNF322A genes in lung cancer patients (Figure 4A)
The ion transport and chromatin remodeling are the two main common biological processes altered in both Asia and Caucasian populations, suggesting that the candidate genes involved in these processes may play important roles in lung tumorigenesis
Summary
Identification and characterization of DNA copy number alteration regions in different racial groups helps to dissect the mechanism of tumorigenesis. There is mounting evidence of difference between Asian and Caucasian lung cancer patients in clinical and epidemiological aspects. Response to certain anticancer treatments such as gefitinib is much greater in Asian patients than Caucasians [4]. These are rare large-scale attempts to identify the molecular characteristics of lung cancer between Asian and Caucasian. Identification and characterization of the chromosome regions with DNA copy number alteration in Western and Asian countries is important to unravel the mechanism underlying lung tumorigenesis
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