Genetic profiling in PCPT: prostate cancer risk, PSA levels, and chemoprevention

PCPT 中的基因分析：前列腺癌风险、PSA 水平和化学预防

基本信息

批准号：
8081838
负责人：
ELIZABETH A. PLATZ
金额：
$ 58.92万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8081838
关键词：
Address Adult Adverse effects Affect Age Alleles Area Under Curve Biology Biopsy Boxing Case-Control Studies Chemoprevention Clinic Clinical Collaborations Complement Data Detection Diagnosis Diagnostic Diet Disease Double-Blind Method Environment Epidemiologist European Family Finasteride Future General Population Genetic Genetic Risk Genetic screening method Genotype Gleason Grade for Prostate Cancer Goals Health Incidence Individual Joints Letters Life Style Logistic Regressions Logistics Malignant neoplasm of prostate Measures Modeling Nature Odds Ratio Oncologist PSA level PSA screening Paper Performance Phase Placebo Control Placebos Population Population Study Prevention Prostate Prostate Adenocarcinoma Prostate Cancer Prevention Trial Race Randomized Receiver Operating Characteristics Recording of previous events Reporting Research Research Personnel Risk Risk Reduction Sampling Screening for Prostate Cancer Screening procedure Staging Stratification Testing Treatment Cost Variant Work arm base cancer diagnosis cancer genetics cancer risk cohort design double-blind placebo controlled trial experience genetic association genetic profiling genetic variant genome wide association study high risk men improved innovation interest member men men&apos s group mortality prevent prospective prostate cancer prevention statistics urologic

项目摘要

DESCRIPTION (provided by applicant): More than a dozen SNPs have been found to be associated with prostate cancer (PCa) risk by genome-wide association studies (GWAS). These reported PCa risk associated SNPs, if not driven by PSA detection bias or not completely correlated with PSA, could be used to improve PSA and other existing clinical variables in predicting positive prostate biopsy (i.e. PCa). These two important questions, however, cannot be addressed by most PCa case-control studies because some cases were diagnosed on the basis of elevated PSA levels. Only studies such as the Prostate Cancer Prevention Trial (PCPT) where men at the end of the trial were biopsied regardless of PSA levels can be used to dissect these two questions. The overall hypothesis of the study is that multiple genetic variants, when combined, can be used to predict men at increased risk for PCa. Specifically, we hypothesize that 1) a subset of genetic variants are associated with PCa risk and are not solely due to PSA detection bias, 2) these genetic variants, when combined, are strongly associated with PCa risk, 3) genetic variants can supplement PSA and other existing clinical variables to improve the predictive performance for PCa and aggressive PCa, and 4) the chemoprevention effect of finasteride is different among men with different genetic risks and the reduction in PCa diagnosis by finasteride is larger for men with higher genetic risk. To test these hypotheses, we will use data and samples from the PCPT study, a phase III randomized, double-blind, placebo-controlled trial of finasteride in the prevention of prostate cancer. We have three specific aims. Aim 1 is to test whether reported prostate cancer risk associated variants from GWAS are associated with PCa risk, free of PSA detection bias. Aim 2 is to estimate the joint predictive performance for prostate cancer diagnosis, overall PCa and aggressive PCa, using genetic variants as well as PSA and other existing clinical variables. Aim 3 is to assess the differential chemoprevention effect of finasteride on prostate cancer diagnosis among men with higher or lower genetic risk for PCa. Results from this study may potentially benefit millions men. Men at highest risk for PCa could be identified at an early age for intensive screening and chemoprevention such as finasteride. Genetic variants could also be used in combination with PSA and other existing clinical variables to considerably improve their predictive accuracy for positive prostate biopsy. PUBLIC HEALTH RELEVANCE: Dozens of prostate cancer risk associated variants, when combined, could be used to identify men at highest risk for prostate cancer. Such men could be identified at an early age for intensive screening and chemoprevention. Prostate cancer risk associated variants could also be used in combination with PSA and other existing clinical variables to considerably improve their predictive accuracy for positive prostate biopsy. 1

描述（由申请人提供）：通过基因组关联研究（GWAS），发现超过十几个SNP与前列腺癌（PCA）风险相关。这些报道的PCA风险相关SNP，如果不受PSA检测偏置或与PSA完全相关的驱动，则可以用于改善PSA和其他现有的临床变量，以预测前列腺活检阳性（即PCA）。但是，大多数PCA病例对照研究无法解决这两个重要问题，因为某些病例是根据PSA级别诊断的。只有前列腺预防试验（PCPT）之类的研究，无论PSA水平如何，都可以在试验结束时进行活检，以剖析这两个问题。该研究的总体假设是，合并后，多种遗传变异可以预测患有PCA风险增加的男性。具体而言，我们假设1）遗传变异的子集与PCA风险相关，而不仅仅是由于PSA检测偏差而引起的，2）这些遗传变异在合并后，与PCA风险密切相关，3）遗传变异可以补充PSA和其他现有的临床变量，以改善PCA的预测性能，以及对PCA的预测性效果，以及对PCA的预测性效果，以及4）的范围。对于遗传风险较高的男性，遗传风险和PCA诊断的降低较大。为了检验这些假设，我们将使用PCPT研究中的数据和样本，这是一项III期随机，双盲，安慰剂对照试验，以预防前列腺癌。我们有三个具体的目标。 AIM 1是测试GWAS的前列腺癌风险与PCA风险相关的前列腺癌风险是否与PSA检测偏置有关。 AIM 2是使用遗传变异以及PSA和其他现有临床变量估算前列腺癌诊断，整体PCA和侵略性PCA的联合预测性能。目标3是评估非那雄胺对PCA遗传风险较高或更低的男性前列腺癌诊断的差异化学预防作用。这项研究的结果可能有可能使数百万男性受益。可以在很小的时候确定有PCA风险最高的男性，以进行强化筛查和化学预防（例如非那雄胺）。遗传变异也可以与PSA和其他现有临床变量结合使用，以大大提高其对阳性前列腺活检的预测准确性。公共卫生相关性：几十个前列腺癌风险相关的变体可用于识别前列腺癌风险最高的男性。可以在很小的时候确定此类男人进行密集筛查和化学预防。前列腺癌风险相关的变体也可以与PSA和其他现有临床变量结合使用，以大大提高其对阳性前列腺活检的预测准确性。 1

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A comparison of Bayesian and frequentist approaches to incorporating external information for the prediction of prostate cancer risk.

DOI：
10.1002/gepi.21600
发表时间：
2012-01
期刊：
GENETIC EPIDEMIOLOGY
影响因子：
2.1
作者：
Newcombe, Paul J.;Reck, Brian H.;Sun, Jielin;Platek, Greg T.;Verzilli, Claudio;Kader, A. Karim;Kim, Seong-Tae;Hsu, Fang-Chi;Zhang, Zheng;Zheng, S. Lilly;Mooser, Vincent E.;Condreay, Lynn D.;Spraggs, Colin F.;Whittaker, John C.;Rittmaster, Roger S.;Xu, Jianfeng
通讯作者：
Xu, Jianfeng

Utility of genome-wide association study findings: prostate cancer as a translational research paradigm.

全基因组关联研究结果的效用：前列腺癌作为转化研究范式。