The −251T Allele of the Interleukin-8 Promoter Is Associated with Increased Risk of Gastric Carcinoma Featuring Diffuse-Type Histopathology in Chinese Population

Abstract

Purpose: Persistent interleukin-8 (IL-8) production contributes to chronic inflammation of the stomach. The proinflammatory IL-1h polymorphisms, which enhance the cytokine production, are associated with increased risk of gastric cancer. The À251A/T polymorphism of the IL-8 promoter is involved in several human diseases. Particularly, the À251A is associated with decreased risk of colorectal cancer. We aimed to determine whether the À251 allele resulting in high IL-8 expression was associated with increased risk of gastric carcinoma. Experimental Design: The À251A/T promoters were cloned and analyzed by luciferase assay. Binding of nuclear proteins to the À251A/T promoters was analyzed by electrophoretic mobility shift assay.The À251A/T promoters were differentiated by PCR-RFLP. Comparison of gastric cancer risk between the À251A/T promoters was done by a case-control study. Results:The À251Tallele possessed transcriptional activity 2-to 5-fold stronger than the À251A counterpart. Electrophoretic mobility shift assay showed that the À251A promoter had strong ability to bind to an unknown protein or multiprotein complex. The À251T allele was associated with increased risk of noncardia (P trend = 0.012) and cardia (P trend = 0.029) carcinomas. Gastric carcinoma patients with the low-risk AA genotype had a tendency to sustain intestinal-type carcinomas (m 2 = 6.816; P = 0.033); however, the high-risk À251Tallele was associated with >2-fold increased risk of diffuse-type (AA versus AT + TT: odds ratio, 2.52; 95% confidence interval,1.16-5.49; P = 0.017) and mixed-type (AA versus AT + TT: odds ratio, 2.22; 95% confidence interval, 1.12-4.40; P = 0.019) carcinomas. Conclusions:The IL-8 À251Tallele is significantly associated with increased risk of gastric carcinoma, particularly the diffuse and mixed types in Chinese population.

Interleukin-4 and -8 Gene Polymorphisms and Risk of Gastric Cancer in a Population in Southwestern China

“…Our result for the overall GC risk was inconsistent with that from two other studies in Eastern and Southeastern China (Zeng et al, 2005), Northern China (Lu et al, 2005), and Chinese Taiwan (Lee et al, 2005); in former two studies, AA was suggested as a hazard genotype for GC, while TT rendered a risk in the Taiwan study. This indicates possible ORs and 95%CIs were calculated by conditional logistic regression and cOR stands for crude odds ratio.…”

“…In addition, these studies adjusted different confounding factors (Lee et al, 2005) or apparently ignored potential confounding from lifestyle or environmental factors for overall analysis (Lu et al, 2005;Zeng et al, 2005), so the results might not be comparable to some extent.…”

“…To date, although multiple studies have been conducted on association of IL4-590 C>T (Loh et al, 2009;Sugimoto et al, 2010;Zhang et al, 2013) and IL8-251 T>A (Gianfagna et al, 2008;Gao et al, 2010;Liu et al, 2010;Wang et al, 2010;Persson et al, 2011;Yuzhalin, 2011;Wang et al, 2012;Xue et al, 2012) and GC among Asians, Caucasians and Hispanics, results are hardly conclusive with evident variability according to race. Even within the Chinese population, studies report conflicting results among studies in Taiwan (Wu et al, 2003;Lai et al, 2005;Lee et al, 2005), Fujian (Lin, 2008), Hebei (Zhang et al, 2010), Beijing (Lu et al, 2005), Guangdong and Shanxi (Zeng et al, 2005) for each polymorphism. Noticing the variability of results, we considered that it was necessitated to initiate a study on IL4-590 C>T and IL8-251T>A for risk of GC in the southwestern region of China.…”

Inflammation, atrophy, and gastric cancer

“…Later studies also determined genetic polymorphisms in TNF-a and IL-10, which, when combined with proinflammatory IL-1β gene cluster polymorphisms, result in a high-risk genotype with a 27-fold or greater risk of developing gastric cancer (67). Studies have also identified the -251T allele in the IL-8 promoter as significantly associated with an increased risk of gastric cancer (68,69). These observations provide strong evidence for host genetics in determining progression to gastric cancer and strengthen the connection between the inflammatory response and the development of gastric atrophy.…”

Treatment of synchronous adenocarcinoma and lymphoma of the stomach: A case report

“…Among individuals infected by H. pylori, ~1-2% may develop gastric cancer, including adenocarcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma (3,6,7). Risk factors include the strain of H. pylori, the duration of the infection, host genetic polymorphisms, and diet or other environmental factors (8)(9)(10)(11)(12)(13). In cases with synchronous adenocarcinoma and lymphoma, H. pylori infection was present in 92% of the cases in Eastern countries and 68% of the cases in Western countries (14), although it remains rare for synchronous tumors.…”