Polymorphisms in MGMT and DNA repair genes and the risk of esophageal adenocarcinoma

Doecke, James, Zhao, Zhen Zhen, Pandeya, Nirmala, Sadeghi, Shahram, Stark, Mitchell, Green, Adele C., Hayward, Nicholas K., Webb, Penlope M. and Whiteman, David C. (2008) Polymorphisms in MGMT and DNA repair genes and the risk of esophageal adenocarcinoma. International Journal of Cancer, 123 1: 174-180. doi:10.1002/ijc.23410


Author Doecke, James
Zhao, Zhen Zhen
Pandeya, Nirmala
Sadeghi, Shahram
Stark, Mitchell
Green, Adele C.
Hayward, Nicholas K.
Webb, Penlope M.
Whiteman, David C.
Title Polymorphisms in MGMT and DNA repair genes and the risk of esophageal adenocarcinoma
Journal name International Journal of Cancer   Check publisher's open access policy
ISSN 0020-7136
Publication date 2008-07-01
Year available 2008
Sub-type Article (original research)
DOI 10.1002/ijc.23410
Open Access Status Not yet assessed
Volume 123
Issue 1
Start page 174
End page 180
Total pages 7
Place of publication Hoboken, NJ, United States
Publisher John Wiley & Sons
Language eng
Subject 970111 Expanding Knowledge in the Medical and Health Sciences
111203 Cancer Genetics
Abstract Rates of adenocarcinoma of the esophagus (EAC) and esophagogastric junction (EGJAC) have increased rapidly in recent decades. The primary risk factors, gastro-esophageal acid reflux and smoking, are potentially genotoxic through the 6 generation of N-nitroso compounds. The DNA repair protein O-6-methylguanine-DNA methyltransferase (MGMT) is the major cellular defense against alkylating DNA damage. We compared patients with EAC (n = 263) or EGJAC (n = 303) with matched population controls (n = 1,337) for the frequency of 5 MGMT single nucleotide polymorphisms (SNPs) (rs12269324, rs12268840, L84F, I143V, K178R), as well as SNPs in DNA repair genes ERCC1 (N118N), XRCC1 (Q399R) and XPD (K751Q). Relative risks were estimated using multivariable logistic regression. Potential biological interaction was assessed through the synergy index S. Each MGMT SNP conferred increased risks of EAC but not EGJAC; strongest associations were found for the 2 variant MGMT alleles rs12268840 and I143V (p = 0.005 and p < 0.001, respectively). Homozygous carriers of MGMT rs12268840 with frequent acid reflux had significantly higher risks of EAC (OR 15.5, 95% CI 5.8-42) than expected under an additive model, consistent with biological interaction (S = 33, 95% CI 1.1-10). Modest, nonsignificant interactions with smoking were also observed. Homozygous variant ERCC1 genotype was associated with reduced risks of EAC (OR 0.6, 95% CI 0.4-1.1), while the homozygous variant XRCC1 genotype conferred higher risks of EGJAC (OR 1.6, 95% CI 1.1-2.4). No associations with EAC or EGJAC were observed with XPD (rs13181). In summary, MGMT SNPs are associated with increased risks of EAC. Exposure to acid reflux, and possibly smoking, confer markedly higher risks among homozygous variant genotype carriers. (C) 2008 Wiley-Liss, Inc.
Keyword Oncology
Oncology
ONCOLOGY
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2009 Higher Education Research Data Collection
School of Medicine Publications
 
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Created: Wed, 15 Apr 2009, 20:10:26 EST by Amanda Jones on behalf of Medicine - Royal Brisbane and Women's Hospital