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是癌变的标志，微量营养素和遗传学相互作用保护基因组免受这一有害过程的影响。最近来自我们小组和其他人的证据表明，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个特定目标，我们将扩展这些发现，并研究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、GPX1、GSTM1、GSTT1、XRCC1、OGG1）是否与：（目标1）前列腺癌临床表型；（目标2）前列腺肿瘤基因组不稳定性；（目标3）复发/进展风险相关。Gleason评分在诊断（活检）将反映临床表型；整体肿瘤拷贝数畸变表明肿瘤基因不稳定。我们将评估1000名来自现有研究的男性，他们被诊断为偶发性局部/区域前列腺癌，在治疗前捐献血液和组织用于研究目的，并同意随访。我们假设较低的循环番茄红素、总类胡萝卜素、α -和γ -生育酚、硒和特定基因变异与Gleason评分、肿瘤基因组不稳定性和复发/进展风险增加有关。我们还假设这些循环的抗氧化剂和基因变异将相互作用，影响疾病的侵袭性和病程。该项目的目的是确定癌症起始后抗氧化营养是否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)科学的新颖性和重要性；2)在现有研究基础上的效率；3)临床和公共卫生的相关性；4)多学科合作研究团队；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.