Genetic and Endocrine Pathways Linking Obesity with Prostate Cancer

描述(申请人提供)：前列腺细胞对雌激素、胰岛素和其他在男性中主要受脂肪量调节的因素做出反应。最近的几项研究报告，肥胖与高级别前列腺癌、进展和死亡率有关，但与PSA时代常见的低级别癌症的相关性仍不清楚。挑战包括测量脂肪沉积模式，从对照组中排除潜伏性癌症，以及控制与肥胖对前列腺癌检测的影响相关的几个潜在偏差。我们的研究旨在应对这些挑战，并确定总肥胖(例如BMI、雌激素)和内脏肥胖(例如腰围、腰臀比、胰岛素)之间的关系，涵盖高级别癌症、低级别癌症和前列腺上皮内瘤变(PIN)。初步分析(R21 CA98348，n=304例癌症，120例PIN，424例对照)发现WHR与PIN显著相关(WHR&gt；1.03：OR=4.75 95%CI(1.71，13.2)，调整PSA、BMI、前列腺体积、年龄种族、矿石结果、核心数)。此外，BMI&GT；35与高级别(Gleasons7)癌相关(ORadj=3.49(0.84，14.4)，P趋势=0.05)。因此，内脏肥胖和相关的代谢综合征可能会影响前列腺癌的早期发生，而与较大的BMI相关的雌激素丰富的环境可能会加速向高级别/临床相关疾病的进展。使用我们建立的多中心快速招募方案，我们将再招募1106名前列腺癌患者(42%的Gleason&7)，435名PIN病例，以及1544名在前列腺活检时没有癌症或PIN的对照组。在诊断前收集数据和样本(饮食、体力活动和其他危险因素的问卷调查；BMI、腰围、坐高和体脂百分比(BIA)的身体测量；血液DNA和激素水平)。代表总肥胖症(如LEP、LEPR、CYP19、ER、AR、SHBG)或内脏肥胖症(RES、ADIP、ADIPR1/2、INS、IRS1/2、IGF1、IGFBP3、PPARy2)与PIN或癌症相关的基因将用多变量Logistic回归进行研究。此外，我们将在单独匹配的分析中调查肥胖和PIN的血液标记物(总肥胖症：瘦素、E2/T比率、SHBG；内脏肥胖症：HbA1c、脂联素、抵抗素)。肥胖症在美国很流行，前列腺癌是癌症相关死亡的主要原因。正在进行的针对PIN的化学预防研究，我们的结果可能会发现新的基于肥胖的预防方法或改善前列腺癌患者的预后。

DESCRIPTION (provided by applicant): Prostate cells respond to estrogens, insulin, and other factors largely regulated in men by adipose mass. Several recent studies report obesity associated with high-grade prostate cancer, progression, and mortality, however the association with low-grade cancer common in the PSA era remains unclear. Challenges include measuring fat deposition patterns, excluding latent cancer from control groups, and controlling for several potential biases associated the effects of obesity on prostate cancer detection. Our study aims to address these challenges and determine the relationship between total adiposity (e.g., BMI, estrogens) and visceral adiposity (e.g., waist circumference, WHR, insulin) across high-grade cancer, low-grade cancer, and prostatic intraepithelial neoplasia (PIN). Preliminary analyses (R21 CA98348, n=304 cancer, 120 PIN, 424 controls) found WHR significantly associated with PIN (WHR>1.03: OR = 4.75 95% Cl (1.71, 13.2), ptrend<0.01, adjusted for PSA, BMI, prostate volume, age race, ORE result, # cores). Also, BMI>35 was associated with high-grade (Gleasons7) cancer (ORadj=3.49 (0.84, 14.4), ptrend = 0.05). Thus, visceral adiposity and the related metabolic syndrome may impact early prostate carcinogenesis, while an estrogen- rich environment associated with greater BMI may accelerate progression to high-grade/clinically relevant disease. Using our established multi-centered rapid-recruitment protocol, we will recruit an additional 1,106 prostate cancer cases (42% Gleason &7), 435 PIN cases, and 1,544 controls without cancer or PIN at prostate biopsy. Data and specimens (questionnaires for diet, physical activity, and other risk factors; body measures for BMI, WHR, sitting height, and % body fat (BIA); blood for DNA and hormone levels) are collected before diagnosis. Genes representing pathways linking total adiposity (e.g., Lep, LepR, CYP19, ER,AR, SHBG) or visceral adiposity (Res, Adip, AdipR1/2, INS, IRS1/2, IGF1, IGFBP3, PPARy2) to PIN or cancer will be investigated using multivariable logistic regression. Also, we will investigate blood markers of adiposity and PIN in an individually matched analysis (total adiposity: leptin, E2/T ratio, SHBG; visceral adiposity: HbA1c, adiponectin, resistin). Obesity is epidemic in the U.S., and prostate cancer is a leading cause of cancer-related death. Ongoing chemoprevention studies target PIN, and our results may identify new obesity-based prevention approaches or improve the prognosis of prostate cancer patients.