Genetic and Endocrine Pathways Linking Obesity with Prostate Cancer

描述（由申请人提供）：前列腺细胞对雌激素、胰岛素和其他主要由脂肪量调节的因素有反应。最近几项研究报告肥胖与高级别前列腺癌、进展和死亡率相关，但与PSA时代常见的低级别前列腺癌的关系尚不清楚。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影响相关的几种潜在偏差。我们的研究旨在解决这些挑战，并确定高级别癌症、低级别癌症和前列腺上皮内瘤变（PIN）患者的总脂肪（如BMI、雌激素）和内脏脂肪（如腰围、腰高比、胰岛素）之间的关系。初步分析（R21 CA98348, n=304名癌症患者，120名正常患者，424名对照组）发现WHR与PIN显著相关（WHR bb0 1.03: OR = 4.75 95% Cl (1.71, 13.2), ptrend<0.01，经PSA、BMI、前列腺体积、年龄、种族、ORE结果、# cores校正后）。此外，BMI bbbb35与高级别（Gleasons7）癌相关（ORadj=3.49 (0.84, 14.4), ptrend = 0.05）。因此，内脏肥胖和相关的代谢综合征可能影响早期前列腺癌的发生，而雌激素丰富的环境与较高的BMI相关可能加速向高级别/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，我们将招募额外的1,106例前列腺癌患者（42% Gleason &7）， 435例PIN病例和1,544例无癌或前列腺活检PIN的对照组。数据和样本(饮食、体力活动和其他危险因素的问卷调查；BMI、WHR、坐姿高度和体脂率（BIA）的身体测量；在诊断前采集血样检测DNA和激素水平。将使用多变量逻辑回归研究代表总肥胖（例如，Lep, LepR, CYP19， ER，AR， SHBG）或内脏肥胖（Res, Adip, AdipR1/2， INS, IRS1/2, IGF1, IGFBP3, PPARy2）与PIN或癌症相关途径的基因。此外，我们将在单独匹配分析中研究肥胖和PIN的血液标志物（总肥胖：瘦素，E2/T比率，SHBG；内脏肥胖：HbA1c，脂联素，抵抗素）。肥胖在美国是一种流行病，前列腺癌是癌症相关死亡的主要原因。正在进行的化学预防研究以PIN为目标，我们的研究结果可能确定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.