The Interaction of Four Genes in the Inflammation Pathway Significantly Predicts Prostate Cancer Risk

Abstract

It is widely hypothesized that the interactions of multiple genes influence individual risk to prostate cancer. However, current efforts at identifying prostate cancer risk genes primarily rely on single-gene approaches. In an attempt to fill this gap, we carried out a study to explore the joint effect of multiple genes in the inflammation pathway on prostate cancer risk. We studied 20 genes in the Toll-like receptor signaling pathway as well as several cytokines. For each of these genes, we selected and genotyped haplotype-tagging single nucleotide polymorphisms (SNP) among 1,383 cases and 780 controls from the CAPS (CAncer Prostate in Sweden) study population. A total of 57 SNPs were included in the final analysis. A data mining method, multifactor dimensionality reduction, was used to explore the interaction effects of SNPs on prostate cancer risk. Interaction effects were assessed for all possible n SNP combinations, where n = 2, 3, or 4. For each n SNP combination, the model providing lowest prediction error among 100 cross-validations was chosen. The statistical significance levels of the best models in each n SNP combination were determined using permutation tests. A four-SNP interaction (one SNP each from IL-10, IL-1RN, TIRAP, and TLR5) had the lowest prediction error (43.28%, P = 0.019). Our ability to analyze a large number of SNPs in a large sample size is one of the first efforts in exploring the effect of high-order gene-gene interactions on prostate cancer risk, and this is an important contribution to this new and quickly evolving field. (Cancer Epidemiol Biomarkers Prev 2005;14(11):2563 -8)

Combinations of Cytochrome P450 Gene Polymorphisms Enhancing the Risk for Sporadic Colorectal Cancer Related to Red Meat Consumption

“…Our present work illustrates the need to go beyond the analysis of single SNPs proposed in most of the current studies on genetic predisposition for complex diseases like cancer. Studies on predisposition to colorectal and prostate cancer have already started to show the power of combinative approaches (49)(50)(51)(52). In addition, our present data highlight the very interest of analyzing SNP combinations in connection with environmental risk factors to a better appreciation of the complexity of in vivo events accounting for cancer susceptibility.…”

Toll-like receptors and immune regulation: implications for cancer therapy

“…For example, IL-1, IL-6, IL-8 and TGF-b released by immune cells and tumor cells promote angiogenesis, tumor growth and the differentiation of Th1, Th17 and Treg cells. Recent studies show that TLR and IL-1 receptor-associated kinases (IRAK) sequence polymorphism is an important risk factor for prostate cancer Xu et al, 2005a). Chronic inflammation induced by Helicobacter pylori infection is the leading cause of stomach cancer, while inflammatory bowel diseases including ulcerative colitis and Crohn's disease are closely associated with colon cancer (Coussens and Werb, 2002;Karin et al, 2006).…”

IL-10 polymorphisms and prostate cancer risk: a meta-analysis

“…3,4,5 Recent studies suggest that genetic polymorphisms of genes involved in innate immunity and chronic inflammation, including the anti-inflammatory cytokine interleukin-10 (IL-10), might impact susceptibility to PCa. 6,7 The IL-10 gene is comprised of five exons, spans B5.2 kb and is located at 1q31-1q32. 8 IL-10 is a pleiotropic cytokine with both anti-inflammatory and antiangiogenic properties.…”