Seminar article Genetic variability in inflammation pathways and prostate cancer risk Jielin Sun, Ph.D. a , Aubrey Turner, M.S. a , Jianfeng Xu, M.D., Dr.PH. a , Henrik Grönberg, M.D. b , William Isaacs, Ph.D. c, * a Center for Human Genomics, Wake Forest University, Winston-Salem, NC 27157, USA b Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden c Department of Urology, Johns Hopkins University, Baltimore, MD 21287, USA Abstract Genetic susceptibility to prostate cancer has been consistently observed by a large number of studies. Recently, several pieces of evidence obtained from epidemiological and pathological studies support that chronic inflammation in prostate tissues may play a role in prostate cancer development. Multiple genes that play critical roles in inflammatory pathways have been associated with prostate cancer risk. In this article we review the key genetic findings of the associated genes. This includes 2 genes identified through family studies, ribonuclease L (RNASEL) and macrophage scavenger receptor 1 (MSR1), as well as a number of genes suggested by case-control studies, such as macrophage inhibitory cytokine-1 (MIC-1), interleukins (IL-8, IL-10), vascular endothelial growth factor (VEGF), intercellular adhesion molecule (ICAM), and Toll-like receptors (TLR-4, TLR-1-6-10 gene cluster). Overall, recent studies seem to suggest multiple genes work together to increase prostate risk, and this is consistent with the reality that inflammation is a very complex process. Thus, future studies are expected to place an emphasis on the study of gene-gene interactions. Advances in high throughput genotyping, data mining, and algorithm development are needed in order to produce interpretable results. © 2007 Elsevier Inc. All rights reserved. Keywords: Genetic variability; Inflammation; Prostate cancer; SNP; Mutation; RNASEL; MSR1; TLR Introduction Because prostate cancer continues to be a major public health burden in the United States and most developed countries, an understanding of the causes of this common cancer is an area of intense interest. Studies of the molecular genetics of a disease can provide an important avenue to identify specific genes and molecular pathways that contrib- ute to the underlying molecular pathogenesis. This article will review efforts to understand genetic predisposition for prostate cancer, with particular emphasis on mounting evi- dence that genetic variability in inflammatory pathways may play a central role in determining and/or modifying prostate cancer susceptibility. Genetic contributions to prostate cancer risk Multiple lines of evidence support an important role for genetics in determining risk for prostate cancer. Many stud- ies have consistently shown family history as an important risk factor for prostate cancer, using either retrospective or cohort study designs [1]. Specifically, prostate cancer risk increases among men who have increasing numbers of first and second-degree relatives diagnosed with prostate cancer, particularly those diagnosed at a young age. That a substan- tial portion of familial prostate cancer is caused by genetic factors is suggested by twin studies, with higher concor- dance rates for prostate cancer in monozygotic twins com- pared to dizygotic twins being consistently observed [2– 4]. By fitting patterns of familial aggregation of a disease in the general population with several alternative modes of inheritance (e.g., a major gene model, an environmental model, and/or polygene model), segregation analysis can provide inferences as to the specific model that best de- scribes the transmission of the disease in families. Multiple segregation analyses of prostate cancer have been per- formed, and the results have been quite consistent and can be summarized as follows: at least some fraction of prostate cancer is likely caused by dominantly acting, rare, high-risk alleles; such alleles appear to act on a significant polygenic background [5– 8]. An early estimate of the number of cases of prostate cancer that may caused by the action of such * Corresponding author. Tel.: 1-410-955-2518; fax: 1-410-502- 9336. E-mail address: wisaacs@jhmi.edu (W. Isaacs). Urologic Oncology: Seminars and Original Investigations 25 (2007) 250 –259 1078-1439/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.urolonc.2006.10.001