Abstract 2632: Genetic variants of iron-dependent metabolism genes and risk of upper gastrointestinal cancers
Authors: Lin Shih-Wen , Freedman Neal D. , Hu Nan , Tang Ze-Zhong , Wang Lemin , Wang Chaoyu , Ding Ti , Wang Yuan , Fan Jin-Hu , Qiao You-Lin , Wheeler William , Yu Kai , Goldstein Alisa M. , Dawsey Sanford M. , Taylor Philip R. , Abnet Christian C. 
Published: August 2012

Abstract
Objectives: Both iron overload and iron deficiency cause oxidative stress and DNA damage, which increase carcinogenesis risk, especially in the gastrointestinal (GI) tract. In animal models, iron overload causes forestomach tumors, and in epidemiologic studies, high heme iron intake is associated with some upper GI cancers. Hemochromatosis, which results in excessive iron absorption in the GI tract, is also associated with GI cancer. The mechanism of increased cancer risk may involve the impairment of iron-dependent metabolic functions related to genome protection and maintenance. Genetic variants of genes with iron-dependent metabolic functions may confer differential GI cancer risk. Therefore, we comprehensively examined the genetic variants of these genes and risk of esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA) in a high-risk population in China. Methods: We genotyped 249 tag single nucleotide polymorphisms (SNPs) in 23 genes with known iron-dependent metabolic function in 1027 ESCC cases and 752 GCA cases plus 1452 controls from two epidemiologic studies in a high-risk region in China. For all genes as a single pathway and each gene individually, we calculated summary p-values using the adaptive rank truncated product (ARTP) method. For SNPs, logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI). Results: In pathway-based tests, the iron pathway was not associated with either ESCC (p=0.320) or GCA (p=0.550). However, in gene-based tests, HMOX2 (heme oxygenase 2, p=0.018) and BMP2 (bone morphogenetic protein 2, p=0.032) were associated with ESCC risk, and IREB2 (iron-responsive element binding protein 2, p=0.033) was associated with GCA risk. In SNP-based tests, RS235756 (OR=0.78, CI=0.66-0.91) and RS910141 (OR=0.76, CI=0.63-0.93) tagged to BMP2 (linkage disequilibrium of pairwise r2=0.55) were associated with ESCC risk. RS6500609 (OR=1.30, CI=1.08-1.57) tagged to HMOX2 was also associated with ESCC risk. RS12910090 (OR=0.83, CI=0.72-0.94) and RS2568500 (OR=0.83, CI=0.73-0.95) tagged to IREB2 (r2=0.90) were associated with GCA risk. RS11630228 (OR=1.21, CI=1.06-1.38) also tagged to IREB2 (r2&lt;0.38 with two previous SNPs) was associated with GCA risk. Conclusions: The potential link between iron status and differential UGI cancer risk may involve the impairment of iron-dependent metabolic functions, which leads to oxidative stress and DNA damage. The association of SNPs in HMOX2 and BMP2 with ESCC risk and IREB2 with GCA risk suggests that genetic variants of genes with iron-dependent metabolic functions may differentially confer risk of upper GI cancer. Further research is warranted to replicate these findings and elucidate the functional effects of the SNPs in the context of upper GI carcinogenesis to better understand the role of iron overload or iron deficiency in cancer development.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2632. doi:1538-7445.AM2012-2632