The database of chromosome imbalance regions and genes resided in lung cancer from Asian and Caucasian identified by array-comparative genomic hybridization.
BACKGROUND
Cancer-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.


METHODS
Array-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.


RESULTS
We 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.


CONCLUSIONS
Our 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.
Department of Pharmacology and Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, No,1, University Road, Tainan 701, Taiwan.
Fang-Yi
FY
Lo
Jer-Wei
JW
Chang
I-Shou
IS
Chang
Yann-Jang
YJ
Chen
Han-Shui
HS
Hsu
Shiu-Feng Kathy
SF
Huang
Fang-Yu
FY
Tsai
Shih Sheng
SS
Jiang
Rajani
R
Kanteti
Suvobroto
S
Nandi
Ravi
R
Salgia
Yi-Ching
YC
Wang
D044466:Asian People / Q000235:genetics*; D001499:Bayes Theorem; D002869:Chromosome Aberrations; D055028:Comparative Genomic Hybridization; D019295:Computational Biology; D056915:DNA Copy Number Variations; D030541:Databases, Genetic; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D015203:Reproducibility of Results; D044465:White People / Q000235:genetics*