Genotypic and Phenotypic Studies of Inflammation in PCPT

描述(申请人提供)：我们假设慢性前列腺炎症性疾病 会导致前列腺癌的发生。慢性炎症可能是前列腺癌发生的启动者和/或促进者，就像感染相关的肝癌和胃癌以及炎症性肠病中的结肠癌一样。事实上，表现为过度增殖和炎症的萎缩区域，称为增生性炎性萎缩(PIA)病变，在前列腺中很常见。这些损伤可能是再生的，可能是对感染或氧化损伤或缺氧造成的细胞损伤的反应的结果。为了解决这一假设，我们建议评估炎症的组织、循环和遗传标记物、其来源或后遗症与前列腺癌的相关性。前列腺癌病例和研究结束后活检阴性的年龄频率匹配的对照组将从前列腺癌预防试验(PCPT)的参与者中选择。在400例患者和400例对照组的活检切片中，我们将使用免疫组织化学或FISH和图像分析来确定炎症和萎缩的患病率、程度和生物学特征。用酶联免疫吸附试验检测600例患者和600例正常对照血清中沙眼衣原体、阴道毛滴虫等5种感染源的抗体。我们将使用MALDI-TOF对1800例患者和1800名对照进行12个基因的胚系多态分型，这些基因涉及对感染和组织损伤的先天和获得性免疫反应(例如，TLR-4、IFNy、IL-10)。我们将使用Logistic回归来估计前列腺癌和高级别疾病的优势比。我们将与其他项目一起测试协会是否 因暴露于可能改变炎症不良影响的因素而异，包括PCPT研究药物非那雄胺、血清抗氧化剂、性类固醇激素和生长因子的水平。鉴于炎症是明确的干预目标，我们预计拟议的工作将对前列腺癌预防产生重要影响。修订后的项目解决了所有审查者关注的问题，包括PCPT中关于炎症与前列腺癌相关性的新的初步数据以及额外的免疫学专业知识。

DESCRIPTION (provided by applicant): We hypothesize that chronic intraprostatic inflammation contributes to the development of prostate cancer. Chronic inflammation may serve as an initiator and/or promoter of prostate carcinogenesis as it does in infection-associated liver and stomach cancer and in colon cancer in inflammatory bowel disease. Indeed, regions of atrophy showing hyperproliferation and inflammation, called proliferative inflammatory atrophy (PIA) lesions, are common in the prostate. These lesions may be regenerative and may be the result of response to infection or cell trauma due to oxidant damage or hypoxia. To address this hypothesis, we propose to evaluate the association of tissue, circulating, and genetic markers of inflammation, its sources, or sequelae with prostate cancer. Prostate cancer cases and age frequency-matched controls who were negative on an end-of-study biopsy will be selected from among participants in the Prostate Cancer Prevention Trial (PCPT). In biopsy sections from 400 cases and 400 controls, we will determine the prevalence, extent, and biological characteristics of inflammation and atrophy using immunohistochemistry or FISH and image analysis. We will detect antibodies against 5 infectious agents (e.g., Chlamydia trachomatous, Trichomonas vaginalis) by ELISA in serum from 600 cases and 600 controls. We will genotype 1800 cases and 1800 controls for germline polymorphisms in 12 genes involved in the innate and adaptive immune response to infection and tissue damage (e.g., TLR-4, IFNy,IL-10) using MALDI-TOF. We will use logistic regression to estimate the odds ratios of prostate cancer and high-grade disease. Jointly with the other Projects, we will test whether the associations vary by exposure to factors that may alter adverse effects of inflammation, including the PCPT study drug finasteride, levels of serum antioxidants, sex steroid hormones, and growth factors. Given that inflammation is a clear target for intervention, we anticipate that the proposed work will have important implications for prostate cancer prevention. The revised Project addresses all reviewer concerns, including those for new preliminary data on the association of inflammation with prostate cancer in the PCPT and additional immunology expertise.