Inflammatory Pathway Gene Polymorphisms and Risk of Prostate Cancer

炎症通路基因多态性与前列腺癌的风险

• 批准号: 7500774
• 负责人: JANET L STANFORD
• 金额: $ 8.8万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7500774
• 关键词: AKT1 gene; Accounting; Affect; Age; Alcohol consumption; Alleles; American; Androgens; Apoptosis; Biology; Blood; Blood specimen; CXCL12 gene; CXCR4 Receptors; Case-Control Studies; Cell Proliferation; Cells; Characteristics; Chronic; Clinical Data; Complex; Confidence Intervals; Consent; Country; DNA; DNA Damage; Defect; Demographic Factors; Development; Diagnosis; Diagnostic; Diet; Disease; Elderly; Equilibrium; Etiology; Family Cancer History; Family history of; Fostering; Free Radicals; Frequencies; Future; Genes; Genetic; Genetic Polymorphism; Genotype; Gleason Grade for Prostate Cancer; Haplotypes; Histologic; IL6ST gene; IL8 gene; Incidence; Inflammation; Inflammatory; Interleukin-10; Interleukin-6; Interview; Logistic Regressions; Logistics; Malignant Neoplasms; Malignant neoplasm of prostate; Medical History; Medical Surveillance; Modeling; Molecular; Mutation; North America; Obesity; Occupational; Odds Ratio; PSA level; Participant; Pathway interactions; Persons; Play; Population; Prevention; Prevention strategy; Probability; Procedures; Proliferating; Prostate; Prostate Adenocarcinoma; Race; Receptor Gene; Recording of previous events; Recruitment Activity; Registries; Regression Analysis; Risk; Risk Factors; Role; STAT3 gene; Sampling; Screening for Prostate Cancer; Signal Pathway; Single Nucleotide Polymorphism; Site; Smoking; Smoking History; Staging; Symptoms; System; Urogenital Diseases; Variant; base; cancer diagnosis; cancer risk; case control; cytokine; family structure; high risk men; insight; man; men; neoplastic cell; novel; receptor; social; sound; tumor growth

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.

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，但人们对导致该疾病的风险因素或潜在分子缺陷知之甚少。一项新出现的假说表明，前列腺的慢性炎症在前列腺癌的发生和进展中发挥着重要作用。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； 2）炎症与细胞增殖增加有关，从而增加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 损伤的细胞得以存活和增殖。最终，炎症可能会破坏增殖和凋亡之间的正常平衡，从而增加前列腺癌的风险。为了研究炎症与 PCa 相关的作用，我们建议评估与炎症通路相关基因的变异等位基因相关的风险。具体来说，我们提出了PCa与以下基因中的单核苷酸多态性（SNP）和单倍型的关联研究：1）IL-6细胞因子、其受体以及Jak/STAT和PI3K/Akt下游信号通路的基因； 2) CXCL12/SDF-1细胞因子及其受体CXCR4；和，3)Cox-2TNF-a、NF-κB、IL-8和IL-10。拟议的基于人群的病例对照研究将涉及对通过普吉特湾 SEER 登记处确定的 1,457 例经组织学证实的 PCa 病例和 1,352 例无 PCa 病史的年龄频率匹配对照进行基因分型。 1993-1996 年或 2002-2005 年，研究参与者年龄在 40-74 岁之间，当时他们被招募参加之前两项涉及类似面对面访谈和抽血的研究之一。记录有关人口因素、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史的信息。 DNA 样本 (n=2,809) 将在 NHGRI 使用 Applied Biosystems SNPlex(tm) 系统进行基因分型。无条件逻辑回归分析将用于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，格里森评分、疾病阶段、诊断性 PSA 水平）将用于评估 PCa 基因型关联是否因疾病侵袭性而异。这项研究的结果可能提供关于炎症途径如何影响 PCa 风险的新信息，并可能提供新的预防策略的见解。仅今年一年，男性诊断出的所有癌症中就有三分之一是前列腺癌，新增病例达 218,890 例。拟议研究的结果可能有助于深入了解这种复杂疾病的潜在生物学原理，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。由于这项研究是以人群为基础的，因此可以估计与人群中前列腺癌风险相关的任何遗传等位基因的影响。这项研究最大的潜在影响将来自对基因等位基因的鉴定，这些基因能够检测出罹患临床侵袭性前列腺癌的风险较高的男性，这些人可能从加强监测或更积极的治疗中受益最多。