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，但对导致该疾病的风险因素或潜在分子缺陷知之甚少。一种新兴的假说表明，前列腺中的慢性炎症在PCa的发展和进展中起作用。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伤DNA的遗传毒性化合物; 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损伤的细胞存活和增殖。最终，炎症可能通过破坏增殖和凋亡之间的正常平衡来增加PCa风险。为了研究炎症在前列腺癌中的作用，我们建议评估与炎症途径相关基因的变异等位基因相关的风险。具体而言，我们提出了一个关联研究前列腺癌的单核苷酸多态性（SNP）和单倍型在以下基因：1）IL-6细胞因子，其受体，和基因的下游信号通路的Jak/STAT和PI 3 K/Akt; 2）CXCL 12/SDF-1细胞因子及其受体，CXCR 4;和，3）考克斯-2 TNF-α，NF-？B、IL-8和IL-10。拟议的基于人群的病例对照研究将涉及通过普吉特海湾SEER登记研究确定的1，457例组织学证实的PCa病例和1，352例年龄频率匹配的对照，无PCa既往史。研究参与者在1993 -1996年或2002-2005年年龄在40-74岁之间，当时他们被招募参加两项先前的研究之一，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、PCa筛查史（PSA和DRE）、家族癌症史、终生吸烟和饮酒以及终生性史。DNA样本（n= 2，809）将在NHGRI使用Applied Biosystems SNALTM系统进行基因分型。将使用非条件logistic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（例如，Gleason评分、疾病分期、诊断PSA水平）将用于评估PCA基因型关联是否根据疾病侵袭性而不同。这项研究的结果可能提供有关炎症途径如何影响PCa风险的新信息，并可能提供新的预防策略的见解。仅在今年，男性诊断出的所有癌症中就有三分之一是前列腺癌，导致218，890例新病例。这项研究的结果可能会深入了解这种复杂疾病的潜在生物学，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。由于这项研究是基于人群的，因此有可能估计发现与人群中前列腺癌风险相关的任何遗传等位基因的影响。这项研究的最大潜在影响将来自于鉴定能够检测出患临床侵袭性前列腺癌风险较高的男性的遗传等位基因，这些男性可能从增加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.