Minimal deletion regions in lung squamous cell carcinoma: association with abnormality of the DNA double-strand break repair genes and their applications on gene identification and prognostic biomarkers.
BACKGROUND
Lung squamous cell carcinoma (SCC) cells frequently exhibit markers of chromosome instability such as high fractional allelic loss (FAL). We postulated that alterations in the p53 damage responsive gene and in the double-strand break (DSB) repair genes, BRCA1 and XRCC5, are involved in patients with high FAL. In addition, chromosomal deletion analysis enables the delineation of the likely locations of tumor suppressor genes (TSG) and could provide molecular markers for disease classification.


METHODS
To define the minimal deletion regions (MDRs), we used 92 microsatellites spanning 29 regions identified in our previous genome-wide chromosomal deletion study in 36 lung SCC patients to verify the maximal contiguous deletion loci.


RESULTS
Eight MDRs at 2q35, 3p14.1-3p14.3, 3p22.2-p23, 3p25.3-3p26.3, 5q35.1-q35.2, 9p23-p24.1, 13q14.11-q14.2, and 17p13.1-p13.2 were found in lung SCC. The candidate genes GAS7 and OVCA2 in the MDR17pA (17p13.1-p13.2) were further examined for mRNA expression. Low expression of the GAS7 gene in 57% of patients analyzed suggested its importance in lung SCC tumorigenesis. In addition, we found a panel of five microsatellites (D3S1766, D4S2397, D4S2361, D13S175, and D17S974), which can be used as prognostic biomarkers in lung SCC. Furthermore, alteration in more than two genes in DSB repair-related pathways was more apparent in high FAL patients.


CONCLUSIONS
Our results provide biomarkers that may be used for monitoring tumor progression and for positional cloning of new TSGs. Importantly, our data show direct evidence that alterations in DSB repair-related pathways are involved in the genomic instability verified by intensive microsatellites of lung SCC.
Tseng
Ruo-Chia
RC
Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.
Hsieh
Feng-Jen
FJ
Hsu
Han-Shui
HS
Wang
Yi-Ching
YC
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000601:surgery; D053903:DNA Breaks, Double-Stranded; D004265:DNA Helicases; D004260:DNA Repair; D005260:Female; D019398:Genes, BRCA1; D016147:Genes, Tumor Suppressor; D016158:Genes, p53; D006801:Humans; D000072200:Ku Autoantigen; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics* / Q000601:surgery; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016019:Survival Analysis
D014408:Biomarkers, Tumor; D004265:DNA Helicases; C106893:XRCC5 protein, human; D000072200:Ku Autoantigen