权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
7696635
负责人：
ELIZABETH A. PLATZ
金额：
$ 64.1万
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 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7696635
关键词：
Address Adult Affect Age Alleles Area Under Curve Biopsy Case-Control Studies Chemoprevention Clinical Data Detection Diagnosis Diagnostic Disease Double-Blind Method European Family history of Finasteride Future Genetic Genetic Risk Genotype Gleason Grade for Prostate Cancer Goals Incidence Individual Joints Logistic Regressions Logistics Malignant neoplasm of prostate Measures Modeling Odds Ratio PSA level PSA screening Performance Phase Placebo Control Placebos Population Population Study Prostate Prostate Cancer Prevention Trial Race Randomized Receiver Operating Characteristics Reporting Research Personnel Risk Risk Reduction Sampling Screening for Prostate Cancer Screening procedure Staging Stratification Testing Upper arm Variant Work base cancer diagnosis cancer risk cohort design double-blind placebo controlled trial follow-up genetic profiling genetic variant genome wide association study high risk men improved interest men men&apos s group mortality prevent prospective prostate cancer prevention public health relevance statistics

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）：全基因组关联研究（GWAS）发现十几种SNP与前列腺癌（PCa）风险相关。这些报告的PCa风险相关SNP，如果不是由PSA检测偏倚驱动或与PSA不完全相关，则可用于改善PSA和其他现有临床变量，以预测阳性前列腺活检（即PCa）。然而，这两个重要的问题，不能解决大多数前列腺癌的病例对照研究，因为一些病例的诊断的基础上PSA水平升高。只有像前列腺癌预防试验（PCPT）这样的研究，在试验结束时对男性进行活检，而不管PSA水平如何，才能用来分析这两个问题。这项研究的总体假设是，当多种遗传变异结合在一起时，可以用来预测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，并且不仅仅是由于PSA检测偏倚，2）这些遗传变异在组合时与PCa风险强烈相关，3）遗传变异可以补充PSA和其他现有的临床变量以改善PCa和侵袭性PCa的预测性能，（4）不同遗传风险的男性，芬那肽的化学预防作用不同，遗传风险高的男性，芬那肽对前列腺癌诊断的降低作用更大。为了检验这些假设，我们将使用PCPT研究的数据和样本，这是一项关于非那匹德预防前列腺癌的III期随机、双盲、安慰剂对照试验。我们有三个具体目标。目的1是测试GWAS报告的前列腺癌风险相关变体是否与PCa风险相关，无PSA检测偏倚。目的2是使用遗传变异以及PSA和其他现有临床变量来估计前列腺癌诊断、总体PCa和侵袭性PCa的联合预测性能。目的3是评估非那肽对具有较高或较低PCa遗传风险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会使数百万人受益。前列腺癌风险最高的男性可以在早期进行强化筛查和化学预防，如芬普胺。遗传变异也可以与PSA和其他现有的临床变量结合使用，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：数十种与前列腺癌风险相关的变异结合在一起，可以用来识别前列腺癌风险最高的男性。这样的人可以在很小的时候就被发现，进行密集的筛查和化学预防。前列腺癌风险相关的变异也可以与PSA和其他现有的临床变量组合使用，以显著提高其对阳性前列腺活检的预测准确性。1