Genotypic and Phenotypic Studies of Inflammation in PCPT

描述（由申请人提供）：我们假设慢性前列腺内炎症 会导致前列腺癌的发生慢性炎症可作为前列腺癌发生的启动子和/或促进子，如其在感染相关的肝癌和胃癌以及炎性肠病中的结肠癌中所做的那样。事实上，显示过度增殖和炎症的萎缩区域，称为增殖性炎性萎缩（PIA）病变，在前列腺中很常见。这些损伤可能是再生性的，并且可能是由于氧化损伤或缺氧而对感染或细胞创伤的反应的结果。为了解决这一假设，我们建议评估组织，循环和遗传标记的炎症，其来源，或后遗症与前列腺癌的关联。将从前列腺癌预防试验（PCPT）的受试者中选择研究结束活检结果为阴性的前列腺癌病例和年龄频率匹配的对照。在400例病例和400例对照的活检切片中，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。我们将检测针对5种感染因子的抗体（例如，用ELISA法检测600例患者和600例健康对照者血清中沙眼衣原体、阴道毛滴虫的含量。我们将对1800例病例和1800例对照进行基因分型，以检测12个基因的种系多态性，这些基因参与对感染和组织损伤的先天性和适应性免疫反应（例如，TLR-4、IFN γ、IL-10）。我们将使用逻辑回归来估计前列腺癌和高级别疾病的比值比。我们将与其他项目一起测试协会是否 不同的暴露因素可能会改变炎症的不良反应，包括PCPT研究药物芬那肽，血清抗氧化剂，性类固醇激素和生长因子的水平。鉴于炎症是一个明确的干预目标，我们预计这项工作将对前列腺癌的预防产生重要影响。修订后的项目解决了所有评审员关注的问题，包括PCPT中炎症与前列腺癌相关性的新初步数据和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.