Epigenetic inactivation of the chromosomal stability control genes BRCA1, BRCA2, and XRCC5 in non-small cell lung cancer.
OBJECTIVE
Lung cancer cells frequently exhibit marked chromosome instability. We postulated that alterations of the double-strand break repair genes (BRCA1, BRCA2, and XRCC5) might be involved in lung cancer.


METHODS
We examined the loss of protein and mRNA expression and the 5'CpG hypermethylation and allelic imbalance of the BRCA1, BRCA2, and XRCC5 genes in 98 non-small cell lung cancer (NSCLC) samples. Anchorage-dependent growth after reexpression of these genes was examined in a lung cancer cell line that originally lacked BRCA1 and BRCA2 expression.


RESULTS
The data indicated that low protein expression of BRCA1 and BRCA2 was frequent in lung adenocarcinomas (42-44%), whereas low XRCC5 protein expression was more prevalent among squamous cell carcinoma (32%). In addition, low BRCA1 expression was significantly associated with low RB expression, especially in lung adenocarcinoma. Concurrent alterations in XRCC5 and p53 were the most frequent profiles in smoking patients. Importantly, low mRNA and protein expressions of BRCA1, BRCA2, and XRCC5 were significantly associated with their promoter hypermethylation. 5-Aza-2'-deoxycytidine treatment of NSCLC cells showed demethylation and reexpression of the BRCA1 and BRCA2 genes and reduced anchorage-independent growth.


CONCLUSIONS
Our retrospective study provides compelling evidence that low mRNA and protein expression in the BRCA1/BRCA2 and XRCC5 genes occur in lung adenocarcinoma and squamous cell carcinoma, respectively, and that promoter hypermethylation is the predominant mechanism in deregulation of these genes. Alteration of the double-strand break repair pathway, perhaps by interacting with p53 and RB deregulation, is important in the pathogenesis of a subset of NSCLC.
Lee
Ming-Ni
MN
Department of Life Sciences, National Taiwan Normal University, and Division of Thoracic Surgery, Taipei Veterans General Hospital, Taiwan.
Tseng
Ruo-Chia
RC
Hsu
Han-Shui
HS
Chen
Jia-Yang
JY
Tzao
Ching
C
Ho
William L
WL
Wang
Yi-Ching
YC
D000230:Adenocarcinoma / Q000378:metabolism; D001483:Base Sequence; D018287:Carcinoma, Large Cell / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D004265:DNA Helicases / Q000235:genetics*; D019175:DNA Methylation; D004260:DNA Repair; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006801:Humans; D000072200:Ku Autoantigen; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D011401:Promoter Regions, Genetic; D012189:Retrospective Studies
D004265:DNA Helicases; C106893:XRCC5 protein, human; D000072200:Ku Autoantigen