Prostate Microenvironmental & Prostate Cancer Progression

描述（由申请人提供）：前列腺微环境和前列腺癌进展-染色体损伤和基因组不稳定性是致癌的标志，微量营养素和遗传学相互作用以保护基因组免受这种有害过程的影响。我们小组和其他人的最新证据表明，几种抗氧化营养素可以防止前列腺癌的发展，与DNA修复和抗氧化代谢有关的遗传变异可能会改变诊断前抗氧化状态对前列腺癌风险的影响。通过以下3个具体目标，我们将扩大这些发现，并调查是否循环诊断后抗氧化剂（即番茄红素、总类胡萝卜素、α-和γ-生育酚和硒）和基因型（即MnSOD、GPX 1、GSTM 1、GSTT 1、XRCC 1、OGG 1）与：（Aim 1）前列腺癌临床表型：（Aim 2）前列腺肿瘤基因组不稳定性：和（目标3）复发/进展的风险。诊断（活检）时的Gleason评分将反映临床表型;总体肿瘤拷贝数畸变将指示肿瘤生殖不稳定性。我们将评估来自现有研究的1000名男性，这些男性被诊断患有局部/区域性前列腺癌，在治疗前捐献血液和组织用于研究目的，并同意随访。我们推测，较低的循环番茄红素，总类胡萝卜素，α-和γ-生育酚，硒和特定的基因变异将与格里森评分增加，肿瘤基因组不稳定性，复发/进展的风险。我们还假设，这些循环中的抗氧化剂和遗传变异将相互作用，影响疾病的侵袭性和病程。该项目的目标是确定癌症发生后的抗氧化营养是否会影响肿瘤的侵袭性和进展，以及这是否取决于基因型。本研究的优势包括1）科学新奇和重要性，2）在现有研究基础上建立的效率，3）临床和公共卫生相关性，4）多学科合作研究团队，以及5）UGSF和DFCI的优秀资源。这项研究可能会通过为癌症患者制定新的营养指南，或启动针对特定基因型人群的抗氧化剂干预的辅助或新辅助随机临床试验来改善公众健康。

DESCRIPTION (provided by applicant): Prostate microenvironment and prostate cancer progression - Chromosomal damage and genomic instability are hallmarks of carcinogenesis, and micronutrients and genetics interact to protect the genome against this deleterious process. Recent evidence from our group and others suggests that several antioxidant nutrients may protect against the development of prostate cancer, and genetic variants involved with DNA repair and antioxidant metabolism may modify the influence of pre-diagnostic antioxidant status on prostate cancer risk. Through the following 3 Specific Aims, we will expand on these findings and investigate whether circulating post-diagnostic antioxidants (i.e. lycopene, total carotenoids, alpha- & gamma- tocopherol, and selenium) and genotypes (i.e. MnSOD, GPX1, GSTM1, GSTT1, XRCC1, OGG1) are associated with: (Aim 1) prostate cancer clinical phenotype: (Aim 2) prostate tumor genomic instability: and (Aim 3) risk of recurrence/ progression. Gleason score at diagnosis (biopsy) will reflect clinical phenotype; and global tumor copy number aberrations will indicate tumor gerbmic instability. We will evaluate 1000 men from an existing study who were diagnosed with incident localized/regional prostate cancer, donated blood and tissue for research purposes prior to treatment, and consented to follow-up. We hypothesize that lower circulating lycopene, total carotenoids, alpha- & gamma-tocopherol, and selenium and specific gene variants will be associated with increased Gleason score, tumor genomic instability, and risk of recurrence/progression. We also hypothesize that these circulating antioxidants and genetic variants will interact to affect the aggressiveness and course of disease. The goal of this project is to determine whether antioxidant nutrition after cancer initiation influences tumor aggressiveness and progression, and whether this depends on genotype. Strengths of this study include the 1) scientific novelty and importance, 2) efficiency of building on existing studies, 3) clinical and public health relevance, 4) multi-disciplinary collaborative research team, and 5) excellent resources of UGSF and DFCI. This study may lead to improved public health through the development of new nutritional guidelines for cancer patients, or the initiation of adjuvant or neoadjuvant randomized clinical trials of antioxidant interventions, focused on populations with specific genotypes.