| Summary: | 碩士 === 國立臺灣師範大學 === 生命科學研究所 === 92 === BACKGROUND: Since 1982, lung cancer is the leading and second cause of cancer deaths among women and men in Taiwan, respectively. Although the medical science makes rapid progress, the molecular mechanisms involved in lung tumorigenesis in Taiwan remain poorly defined. Alterations of oncogenes, tumor suppressor genes or DNA repair genes have been shown to involve in the multi-steps carcinogenesis of human cancer. Double-strand breaks in DNA are serious threats to genome integrity because they can result in chromosomal aberrations, such as loss of heterozygosity (LOH). AIM: The purpose of this study is to identify the molecular mechanism of alterations of the DNA double-strand break repair (DSBR) genes, BRCA1, BRCA2, and XRCC5, involved in non-small cell lung cancer (NSCLC) tumorigenesis in Taiwan. RESULTS: We found that the frequency of BRCA1 LOH and promoter hypermethylation was 26.3% (20/76) and 31% (27/87), respectively. In addition, 28.7% (25/87) and 29.9% (26/87) NSCLC patients had decreased or loss of BRCA1 protein and mRNA expression, respectively. With regard to BRCA2 gene alteration analyses, we found that the frequency of BRCA2 LOH and promoter hypermethylation was 44.9% (31/69) and 39.1% (34/87), respectively. Note that 36.8% (32/87) NSCLC patients had decreased or loss of BRCA2 mRNA expression. The abnormal BRCA2 expression was found more frequently in adenocarcinoma (P=0.017) and old patients (P=0.035). In addition, we found that the frequency of XRCC5 LOH and promoter hypermethylation was 37.3% (25/67) and 21.8% (19/87), respectively. There were 18.4% (16/87) and 27.6% (24/87) of NSCLC patients had decreased or loss of XRCC5 protein and mRNA expression, respectively. The abnormal XRCC5 expression was found more frequently in squamous carcinoma (SQ, P=0.031) and smoking (P=0.043) patients. Among the 87 NSCLC patients analyzed, alterations in at least one of the DSBR genes were 62.1% (54/87). In addition, we analyzed the protein expression of the damage response gene, p53. It was found that 52.8% (46/87) NSCLC patients with p53 overexpression, and most of them were SQ (P=0.006) and late stage (P=0.044) patients. CONCLUSION: The study was the first report which comprehensively examines the alteration of the DSBR genes, BRCA1, BRCA2, and XRCC5 at DNA, RNA and protein levels in lung tumorigenesis. Our data indicate that the alterations in DSBR involve in NSCLC tumorigenesis in Taiwan.
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