Inflammatory Pathway Gene Polymorphisms and Risk of Prostate Cancer

描述（由申请人提供）：前列腺癌（PCa）在北美的所有癌症中发病率最高，但对导致该疾病的危险因素或潜在分子缺陷知之甚少。一种新出现的假说认为前列腺的慢性炎症在前列腺癌的发生和发展中起作用。炎症可能促进癌症的发展，因为：1)炎症部位的细胞暴露于自由基和其他直接损害DNA的基因毒性化合物中；2)炎症与细胞增殖增加有关，增加了细胞获得新突变的可能性；3)炎症细胞释放抑制细胞凋亡的细胞因子，使dna受损的细胞存活和增殖。最终，炎症可能通过破坏细胞增殖和细胞凋亡之间的正常平衡来增加前列腺癌的风险。为了研究炎症在PCa中的作用，我们建议评估炎症通路相关基因变异等位基因的风险。具体来说，我们提出了PCa与以下基因的单核苷酸多态性（snp）和单倍型的关联研究：1)IL-6细胞因子及其受体，以及Jak/STAT和PI3K/Akt下游信号通路基因；2) CXCL12/SDF-1细胞因子及其受体CXCR4；3) Cox-2 TNF-a, NF-？B， IL-8和IL-10。拟议的基于人群的病例对照研究将包括通过Puget Sound SEER登记处确定的1457例组织学证实的PCa病例和1352例年龄频率匹配的无PCa病史的对照。研究参与者在1993-1996年或2002-2005年期间年龄在40-74岁之间，当时他们被招募参加之前的两项研究中的一项，其中包括类似的面对面访谈和抽血。记录人口统计学因素、病史、前列腺癌筛查史（PSA和DRE）、家族癌症史、终生吸烟和饮酒以及终生性行为史等信息。DNA样本（n=2,809）将在NHGRI使用Applied Biosystems SNPlex（tm）系统进行基因分型。将使用无条件逻辑回归分析来估计与上述遗传多态性相关的比值比和95%置信区间。临床数据（如Gleason评分、疾病分期、诊断性PSA水平）将用于评估前列腺癌基因型相关性是否因疾病侵袭性而异。这项研究的结果可能为炎症途径如何影响PCa的风险提供新的信息，并可能为新的预防策略提供见解。仅今年一年，男性确诊的癌症中就有三分之一是前列腺癌，导致218890例新病例。这项研究的结果可能会为这种复杂疾病的潜在生物学提供深入的见解，并为未来的预防研究提供有用的途径，例如旨在减少炎症的策略。因为这项研究是以人群为基础的，所以有可能估计任何与前列腺癌风险相关的基因等位基因的影响。这项研究最大的潜在影响将来自于基因等位基因的鉴定，这些等位基因能够检测出患有临床侵袭性前列腺癌的高风险男性，这些男性可能从加强监测或更积极的治疗中获益最多。

DESCRIPTION (provided by applicant): Prostate cancer (PCa) has the highest incidence of any cancer in North America, yet little is known about the risk factors or underlying molecular defects that cause the disease. One emerging hypothesis suggests that chronic inflammation in the prostate plays a role in the development and progression of PCa. Inflammation may foster the development of cancer because: 1) cells at the site of inflammation are exposed to free radicals and other genotoxic compounds that directly damage DNA; 2) inflammation is associated with increased cellular proliferation, enhancing the probability that cells may acquire new mutations; and 3) inflammatory cells release cytokines that inhibit apoptosis, allowing DNA-damaged cells to survive and proliferate. Ultimately, inflammation may augment PCa risk by disrupting the normal balance between proliferation and apoptosis. To investigate the role of inflammation in relation to PCa, we propose to evaluate the risk associated with variant alleles of inflammatory pathway-related genes. Specifically, we propose an association study of PCa in relation to single nucleotide polymorphisms (SNPs) and haplotypes in the following genes: 1) IL-6 cytokine, its receptor, and genes of the downstream signaling pathways of Jak/STAT and PI3K/Akt; 2) CXCL12/SDF-1 cytokine and its receptor, CXCR4; and, 3) Cox-2 TNF-a, NF-?B, IL-8 and IL-10. The proposed population-based case-control study will involve genotyping 1,457 histologically confirmed PCa cases identified through the Puget Sound SEER registry and 1,352 age frequency-matched controls with no prior history of PCa. Study participants were 40-74 years old in1993-1996 or 2002-2005 when they were recruited for one of two prior studies that involved similar in-person interviews and blood draws. Information on demographic factors, medical history, PCa screening history (PSA and DRE), family cancer history, lifetime smoking and alcohol consumption, and lifetime sexual history was recorded. DNA samples (n=2,809) will be genotyped at NHGRI using the Applied Biosystems SNPlex(tm) system. Unconditional logistic regression analysis will be used to estimate odds ratios and 95% confidence intervals associated with the above genetic polymorphisms. Clinical data (e.g., Gleason score, stage of disease, diagnostic PSA level) will be used to assess whether PCa-genotype associations differ according to disease aggressiveness. Results from this study may provide novel information on how the inflammatory pathway may affect risk of PCa and may provide insights leading to new prevention strategies. This year alone, a third of all cancers diagnosed in men will be prostate adenocarcinoma, leading to 218,890 new cases. Results from the proposed study may provide insight into the underlying biology of this complex disease and suggest useful avenues for future prevention studies, such as strategies aimed at decreasing inflammation. Because this study is population-based, it will be possible to estimate the impact of any genetic alleles found to be related to prostate cancer risk in the population. The greatest potential impact of this study would result from identification of genetic alleles able to detect men at higher risk of developing clinically aggressive prostate cancer, who might benefit most from increased surveillance or more aggressive treatment.