Polymorphisms in MGMT and DNA Repair Genes and the Risk of Esophageal Adenocarcinoma

Rates of adenocarcinoma of the esophagus (EAC) and esophago-gastric junction (EGJAC) have increased rapidly in recent decades. The primary risk factors, gastro-esophageal acid reflux and smoking, are potentially genotoxic through the 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 = 3.3, 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.