Genetic polymorphisms of phase I and II metabolizing enzymes and susceptibility to esophageal adenocarcinoma.

Z Zheng, MD, a, KA MacDonald, a, D Chiasson, BSc, a, JR Guernsey, PhD, a, DL Guernsey, PhD, a, DC Riddell, MD, a, J McLaughlin, PhD, b, AG Casson, FRCSC, a

a Dalhousie University, Halifax, Nova Scotia, Canada and the University of Toronto, Ontario, Canada

AIM To study genetic polymorphisms of selected Phase I and II metabolizing enzymes (implicated in carcinogen activation, detoxification and DNA repair) in a case-control study, to determine susceptibility to development of primary esophageal adenocarcinoma (EADC). METHODS Cases comprised 45 patients with surgically resected EADC. No patient received induction therapy, and strict clinicopathologic criteria were used to define EADC. PCR-based assays (RFLP/SSCP) were used to genotype cytochrome P450 (CYP) 1A1 [MspI; Ile:Val], microsomal epoxide hydroxylase (mEH) [fast and slow alleles], and glutathione S-transferase (GST) T1, M1 and P1. DNA was extracted from blood of 45 healthy age/sex matched controls from the same geographic region, and polymorphism frequencies compared. RESULTS GST P1 was found at increased frequency in patients (58% vs. 42% for controls; p=0.06). Whereas mEH [slow allele] was found at reduced frequency in patients compared to controls (42% vs. 53%; p=0.03), mEH [fast allele] was seen at increased frequency in patients (38% vs. 25% for controls; p=0.001). Polymorphism frequencies for GST T1, M1, and CYP1A1 were not statistically different between patients and controls. However, two previously unreported CYP1A1 alterations (putative functional mutations) were found in exon 7 in two tumors: codon 440, GAC/Asp>AAC/Asn, and codon 435 (T deletion). CONCLUSIONS We conclude that 1) polymorphisms of GST P1 and mEH may be implicated as risk factors for individual susceptibility to EADC, and 2) the novel CYP1A1 alterations described may be critical early genetic events associated with the development of EADC in selected individuals.

KEY WORDS: esophagus, adenocarcinoma, mEH, .

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Risk Assessment, Part 2.