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Candidate Gene Association Study of Esophageal Squamous Cell Carcinoma in a High-Risk Region in Iran

¹ Digestive Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran; ² Women's College Research Institute and ³ Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; ⁴ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland; ⁵ IARC, Lyon, France; and ⁶ Epidemiology Research Unit Research Centre, CHUM-Hôtel-Dieu, University of Montreal, Montreal, Quebec, Canada

Requests for reprints: Steven A. Narod, Women's College Research Institute, Faculty of Medicine, University of Toronto, 7th Floor, 790 Bay Street, Toronto, Ontario, Canada M5G 1N8. Phone: 416-351-3765; Fax: 416-351-3767; E-mail: steven.narod{at}wchospital.ca.

Key Words: esophageal squamous cell carcinoma • ADH1B • MGMT

There is a region with a high risk for esophageal squamous cell carcinoma (ESCC) in the northeast of Iran. Previous studies suggest that hereditary factors play a role in the high incidence of cancer in the region. We selected 22 functional variants (and 130 related tagSNPs) from 15 genes that have been associated previously with the risk of ESCC. We genotyped a primary set of samples from 451 Turkmens (197 cases and 254 controls). Seven of 152 variants were associated with ESCC at the P = 0.05 level; these single nucleotide polymorphisms were then studied in a validation set of 549 cases and 1,119 controls, which included both Turkmens and non-Turkmens. The association observed for a functional variant in ADH1B was confirmed in the validation set, and that of a tagSNP in MGMT, the association was borderline significant in the validation set, after correcting for multiple testing. The other 5 variants that were associated in the primary set were not significantly associated in the validation set. The histidine allele at codon 48 of ADH1B gene was associated with a significantly decreased risk of ESCC in the joint data set (primary and validation set) under a recessive model (odds ratio, 0.41; 95% confidence interval, 0.29-0.76; P = 4 x 10^–4). The A allele of the rs7087131 variant of MGMT gene was associated with a decreased risk of ESCC under a dominant model (odds ratio, 0.79; 95% confidence interval, 0.64-0.96; P = 0.02). These results support the hypothesis that genetic predisposition plays a role in the high incidence of ESSC in Iran. [Cancer Res 2009;69(20):7994–8000]