Epigenetic inactivation of the chromosomal stability control genes BRCA1 BRCA2, and XRCC5 in non-small cell lung cancer

Ming Ni Lee, Ruo Chia Tseng, Han Shui Hsu, Jia Yang Chen, Ching Tzao, William L. Ho, Yi Ching Wang

Research output: Contribution to journalArticle

81 Citations (Scopus)

Abstract

Purpose: 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. Patients and 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.

Original languageEnglish
Pages (from-to)832-838
Number of pages7
JournalClinical Cancer Research
Volume13
Issue number3
DOIs
Publication statusPublished - Feb 1 2007
Externally publishedYes

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BRCA2 Gene
BRCA1 Gene
Chromosomal Instability
Epigenomics
Non-Small Cell Lung Carcinoma
BRCA1 Protein
Lung Neoplasms
decitabine
Messenger RNA
Squamous Cell Carcinoma
BRCA2 Protein
Allelic Imbalance
Growth
Genes
Proteins
Retrospective Studies
Smoking
Cell Line
Adenocarcinoma of lung

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Epigenetic inactivation of the chromosomal stability control genes BRCA1 BRCA2, and XRCC5 in non-small cell lung cancer. / Lee, Ming Ni; Tseng, Ruo Chia; Hsu, Han Shui; Chen, Jia Yang; Tzao, Ching; Ho, William L.; Wang, Yi Ching.

In: Clinical Cancer Research, Vol. 13, No. 3, 01.02.2007, p. 832-838.

Research output: Contribution to journalArticle

Lee, Ming Ni ; Tseng, Ruo Chia ; Hsu, Han Shui ; Chen, Jia Yang ; Tzao, Ching ; Ho, William L. ; Wang, Yi Ching. / Epigenetic inactivation of the chromosomal stability control genes BRCA1 BRCA2, and XRCC5 in non-small cell lung cancer. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 3. pp. 832-838.
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abstract = "Purpose: 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. Patients and 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.",
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AU - Tseng, Ruo Chia

AU - Hsu, Han Shui

AU - Chen, Jia Yang

AU - Tzao, Ching

AU - Ho, William L.

AU - Wang, Yi Ching

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N2 - Purpose: 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. Patients and 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.

AB - Purpose: 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. Patients and 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.

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