Ostate cancer is the most frequent and second most lethal cancer in men in the United States [1]. There is growing evidence that innate immunity and inflammation may play a role in Fexinidazole biological activity prostate and other cancers [2,3,4]. Chronic inflammation could contribute to prostate cancer through several biological processes: the mutagenesis caused by oxidative stress; the NT-157 custom synthesis remodeling of the extracellular matrix; the recruitment of immune cells, fibroblasts, and endothelial cells; or the induction of cytokines and growth factors contributing to a proliferative and angiogenic environment [2,3,5]. Compelling evidence supports a role for genes involved in the innate immunity and inflammation pathway in prostate cancer risk. Several genes harboring single nucleotide polymorphisms (SNPs) associated with prostate cancer risk have been identified, including: the pattern recognition receptors MSR1, TLR1, TLR4, TLR5, TLR6, and TLR10 [6,7,8,9,10,11,12,13,14,15,16]; the antiviral gene RNASEL [9,17,18,19,20,21]; the cytokines MIC1, IL8, TNFa, and IL1RN [13,22,23,24,25,26]; and the proinflammatory gene COX-2 [27,28,29,30]. However, most of the previous studies have focused on individual SNPs or genes and very little is known about the impact of the overall innate immunity and inflammation pathway on developing more advanced prostate cancer. Moreover, advanced prostate cancer cases have a higher public health burden than less advanced cases. Thus, identifying thecomponents of the innate immunity and inflammatory process that increase the risk of advanced prostate cancer is of major importance. To determine the role of innate immunity and inflammation in advanced prostate cancer, we investigated the association of 320 SNPs, located in 46 innate immunity and inflammation genes, with advanced prostate cancer risk. We undertook a comprehensive approach evaluating the association between disease risk and SNPs-sets pooled across the whole pathway, sub-pathways, and each gene, as well as individual SNPs.Materials and Methods Study PopulationThe case sample comprised 494 men with newly diagnosed, histologically confirmed prostate cancer, having either a Gleason score 7, a clinical stage T2c, or a serum Prostate Serum Antigen (PSA) at diagnosis .10 recruited from the major medical institutions in Cleveland, Ohio (Cleveland Clinic Foundation, University hospitals of Cleveland, and their affiliates) [31]. The control sample comprised 536 men frequency matched to cases by age (within 5 years), ethnicity, and medical institution, who underwent standard annual exams at the major medical institutions in Cleveland, and who did not have a previous history of non-skin cancer. The PSA was measured and found elevated in two controls. Further investigations lead us to reclassify them as advanced cases of prostate cancer, leaving us with a total ofInnate Immunity Inflammation in Prostate CancerTable 1. Study characteristics of the advanced prostate cancer cases and controls.Cases (n = 494) Age (year), 1379592 mean (SD) Ethnicity, n ( ) African American Caucasian Prostate cancer in first degree relative, n ( )b Negative Positive PSA at diagnosis (ng/mL), mean (SD) Categories of PSA at diagnosis, n ( ) ,4.0 4.0?.9 10?9.9 20?9.9 .50 Gleason score, n ( ) #6 3+4 4+3 or 8 Clinical stage, n ( ) T1 T2a-T2b T2c T3a bControls (n = 536) (8.34) 65.85 (8.54)P-value of heterogeneitya 0.65.90(18.2) (81.8)104(19.4) (80.6)0.381 112 14.(77.3) (22.7) (27.67)472 59 1.(88.9) (11.1) (1.71),2610216 ,25 249 152 53.Ostate cancer is the most frequent and second most lethal cancer in men in the United States [1]. There is growing evidence that innate immunity and inflammation may play a role in prostate and other cancers [2,3,4]. Chronic inflammation could contribute to prostate cancer through several biological processes: the mutagenesis caused by oxidative stress; the remodeling of the extracellular matrix; the recruitment of immune cells, fibroblasts, and endothelial cells; or the induction of cytokines and growth factors contributing to a proliferative and angiogenic environment [2,3,5]. Compelling evidence supports a role for genes involved in the innate immunity and inflammation pathway in prostate cancer risk. Several genes harboring single nucleotide polymorphisms (SNPs) associated with prostate cancer risk have been identified, including: the pattern recognition receptors MSR1, TLR1, TLR4, TLR5, TLR6, and TLR10 [6,7,8,9,10,11,12,13,14,15,16]; the antiviral gene RNASEL [9,17,18,19,20,21]; the cytokines MIC1, IL8, TNFa, and IL1RN [13,22,23,24,25,26]; and the proinflammatory gene COX-2 [27,28,29,30]. However, most of the previous studies have focused on individual SNPs or genes and very little is known about the impact of the overall innate immunity and inflammation pathway on developing more advanced prostate cancer. Moreover, advanced prostate cancer cases have a higher public health burden than less advanced cases. Thus, identifying thecomponents of the innate immunity and inflammatory process that increase the risk of advanced prostate cancer is of major importance. To determine the role of innate immunity and inflammation in advanced prostate cancer, we investigated the association of 320 SNPs, located in 46 innate immunity and inflammation genes, with advanced prostate cancer risk. We undertook a comprehensive approach evaluating the association between disease risk and SNPs-sets pooled across the whole pathway, sub-pathways, and each gene, as well as individual SNPs.Materials and Methods Study PopulationThe case sample comprised 494 men with newly diagnosed, histologically confirmed prostate cancer, having either a Gleason score 7, a clinical stage T2c, or a serum Prostate Serum Antigen (PSA) at diagnosis .10 recruited from the major medical institutions in Cleveland, Ohio (Cleveland Clinic Foundation, University hospitals of Cleveland, and their affiliates) [31]. The control sample comprised 536 men frequency matched to cases by age (within 5 years), ethnicity, and medical institution, who underwent standard annual exams at the major medical institutions in Cleveland, and who did not have a previous history of non-skin cancer. The PSA was measured and found elevated in two controls. Further investigations lead us to reclassify them as advanced cases of prostate cancer, leaving us with a total ofInnate Immunity Inflammation in Prostate CancerTable 1. Study characteristics of the advanced prostate cancer cases and controls.Cases (n = 494) Age (year), 1379592 mean (SD) Ethnicity, n ( ) African American Caucasian Prostate cancer in first degree relative, n ( )b Negative Positive PSA at diagnosis (ng/mL), mean (SD) Categories of PSA at diagnosis, n ( ) ,4.0 4.0?.9 10?9.9 20?9.9 .50 Gleason score, n ( ) #6 3+4 4+3 or 8 Clinical stage, n ( ) T1 T2a-T2b T2c T3a bControls (n = 536) (8.34) 65.85 (8.54)P-value of heterogeneitya 0.65.90(18.2) (81.8)104(19.4) (80.6)0.381 112 14.(77.3) (22.7) (27.67)472 59 1.(88.9) (11.1) (1.71),2610216 ,25 249 152 53.
