Genetic and Endocrine Pathways Linking Obesity with Prostate Cancer

肥胖与前列腺癌相关的遗传和内分泌途径

• 批准号: 8107616
• 负责人: Jay H. Fowke
• 金额: $ 52.78万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-28 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8107616
• 关键词: Abdomen; Address; Adipose tissue; Aftercare; Age; Archives; Biolectric Impedance; Biological Markers; Biopsy; Blood; Body fat; Body measure procedure; CYP19A1 gene; Cancer Control; Cancer Detection; Cancer Etiology; Cancer Patient; Case-Control Studies; Cells; Cessation of life; Chemoprevention; Clinic; Control Groups; Country; DNA; Data; Deposition; Detection; Diagnosis; Diagnostic; Diet; Disease; Endocrine; Environment; Epidemic; Estradiol; Estrogens; Fatty acid glycerol esters; Future; Genes; Genetic; Genetic Polymorphism; Gleason Grade for Prostate Cancer; Glycosylated Hemoglobin; Glycosylated hemoglobin A; Height; Hip region structure; Hormones; Hyperinsulinism; IGF1 gene; IGFBP3 gene; IRS1 gene; Insulin; Interleukin-2; Investigation; Leptin; Life Style; Link; Logistic Regressions; Malignant Neoplasms; Malignant neoplasm of prostate; Measurement; Measures; Metabolic syndrome; Molecular; Morbidity - disease rate; Obesity; PSA screening; Pathway interactions; Pattern; Physical activity; Prevention approach; Prostate; Prostatic Intraepithelial Neoplasias; Protocols documentation; Quality of life; Questionnaires; Race; Recruitment Activity; Regulation; Reporting; Research; Research Design; Risk; Risk Factors; Role; SHBG gene; Specimen; Structure; TNF gene; Testosterone; Urine; Urology; Visceral; Waist-Hip Ratio; Weights and Measures; adiponectin; base; cancer therapy; case control; clinically relevant; disorder control; improved; men; migration; mortality; novel; outcome forecast; prostate carcinogenesis; public health priorities; receptor; resistin; steroid hormone; tumor progression; waist circumference

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.

前列腺细胞对脂肪质量对男性的雌激素，胰岛素和其他因素反应。最近的一些研究报告说，与高级前列腺癌，进展和死亡率有关的肥胖症，但是在PSA时代，与低度癌症的关联尚不清楚。挑战包括测量脂肪沉积模式，从对照组中排除潜在癌症以及控制肥胖对前列腺癌检测的影响的几种潜在偏见。我们的研究旨在应对这些挑战，并确定总脂肪（例如BMI，雌激素）和内脏肥胖（例如，腰围，WHR，WHR，胰岛素）在高级癌症，低度癌症和前列腺内上皮内肿瘤（PIN）之间的关系。初步分析（R21 CA98348，n = 304个癌症，120 PIN，424个对照）与PIN显着相关（WHR> 1.03：OR = 4.75 95％Cl（1.71，13.2），Ptrend <0.01，对PSA，BMI，BMI，PROSTATE，PROSTATE量，Prostate Amege Age Age Apea，Age Apeal Race，ore Race，ore Real essec，ore uses，use＃CORES，ORES，＃CORES，＃CORESSERES，＃CORES）调整。另外，BMI> 35与高级（GLEANSEAN7）癌症（Oradj = 3.49（0.84，14.4），Ptrend = 0.05）有关。因此，内脏肥胖和相关的代谢综合征可能会影响早期前列腺癌发生，而与BMI更大的雌激素环境可能会加速发展为高级/临床相关疾病。使用我们既定的以多中心快速恢复方案，我们将招募1,106例前列腺癌病例（42％Gleason和7），435例PIN病例和1,544个没有癌症或PIN的前列腺活检的对照。数据和标本（饮食，身体活动和其他危险因素的问卷； BMI，WHR，坐姿高度和体内脂肪％的身体测量（BIA）； DNA和激素水平的血液）在诊断之前收集。代表连接总肥胖的途径的基因（例如LEP，LEPR，CYP19，ER，AR，SHBG）或内脏肥胖（Res，ADIP，ADIP，ADIPR1/2，INS，IRS1/2，IRS1/2，IGF1，IGF1，IGFBP3，PPARY2，PPARY2）与PIN或癌症将使用Multial Logistic contivaritivaritivaritivarivarivarivarivarivarivarivarivarecression进行研究。此外，我们将在单独匹配的分析中研究肥胖和销钉的血液标志物（总脂肪：瘦素，E2/T比，SHBG；内脏肥胖：HBA1C：HBA1C，脂联素，抵抗素）。肥胖症在美国流行，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针对PIN，我们的结果可能确定了新的基于肥胖症的预防方法或改善了前列腺癌患者的预后。

项目成果

Association between biomarkers of obesity and risk of high-grade prostatic intraepithelial neoplasia and prostate cancer--evidence of effect modification by prostate size.

• DOI: 10.1016/j.canlet.2012.10.010
• 发表时间: 2013-01-28
• 期刊: CANCER LETTERS
• 影响因子: 9.7
• 作者: Fowke, Jay H.;Motley, Saundra;Dai, Qi;Concepcion, Raoul;Barocas, Daniel A.
• 通讯作者: Barocas, Daniel A.

Obesity, body composition, and prostate cancer.

• DOI: 10.1186/1471-2407-12-23
• 发表时间: 2012-01-18
• 期刊: BMC cancer
• 影响因子: 3.8
• 作者: Fowke JH;Motley SS;Concepcion RS;Penson DF;Barocas DA
• 通讯作者: Barocas DA

Association of nonsteroidal anti-inflammatory drugs, prostate specific antigen and prostate volume.

• DOI: 10.1016/j.juro.2009.01.031
• 发表时间: 2009-05
• 期刊: The Journal of urology
• 作者: Fowke JH;Motley SS;Smith JA Jr;Cookson MS;Concepcion R;Chang SS;Byerly S
• 通讯作者: Byerly S

The associations between statin use and prostate cancer screening, prostate size, high-grade prostatic intraepithelial neoplasia (PIN), and prostate cancer.

• DOI: 10.1007/s10552-010-9713-4
• 发表时间: 2011-03
• 期刊: Cancer causes & control : CCC
• 作者: Fowke JH;Motley SS;Barocas DA;Cookson MS;Concepcion R;Byerly S;Smith JA Jr
• 通讯作者: Smith JA Jr