Clinical significance of promoter hypermethylation of DNA repair genes in tumor and serum DNA in invasive ductal breast carcinoma patients

Gayatri Sharma, Sameer Mirza, Rajinder Parshad, Anurag Srivastava, Siddartha Datta Gupta, Pranav Pandya, Ranju Ralhan

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

Aims: The clinical relevance of frequent methylation of CpG islands of key cancer genes in breast cancer is being increasingly recognized. Our study aimed to evaluate the promoter methylation status of DNA repair genes-BRCA1 MGMT and GSTP1 in tumor and circulating DNA of invasive ductal breast carcinoma patients. Main methods: Methylation-specific PCR was carried out to investigate the promoter methylation status of genes in tumor and circulating DNA of 100 breast cancer patients in a prospective study. The effect of promoter methylation on protein expression was evaluated by immunohistochemistry. Key findings: The frequency of tumor hypermethylation was 27% in BRCA1, 32% in MGMT and 25% in GSTP1 and correlated with methylation of these genes in paired serum DNA. Immunohistochemical analysis showed no detectable expression of BRCA1 and MGMT in 51/89 (57%) and 35/89 (39%) tumors, respectively. MGMT promoter methylation mediated gene silencing was associated with loss of its protein expression (p=0.002, O.R.=4.5, 95% C.I.=1.7-12.0). BRCA1 promoter methylation was not associated with loss of its protein expression, indicating that methylation is not the sole mechanism accounting for the loss/reduced BRCA1 protein expression. Importantly, GSTP1 and BRCA1 hypermethylation were found to be independent of other prognostic factors in predicting disease recurrence (p=0.02, HR. =7.6, 95% C.I.=1.4-44.1; p=0.04, HR. =6.2, 95% C.I.=1.1-35.7). Significance: Our study underscores the potential utility of DNA methylation of these genes in serum as a promising biomarker and can serve as a surrogate for tumor DNA methylation for diagnosis and prognosis of breast cancer.

Original languageEnglish (US)
Pages (from-to)83-91
Number of pages9
JournalLife Sciences
Volume87
Issue number3-4
DOIs
StatePublished - Jul 1 2010

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Keywords

  • BRCA1
  • Breast cancer
  • DNA methylation
  • GSTP1
  • Gene silencing
  • MGMT

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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