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

描述（由申请人提供）：通过全基因组关联研究（GWAS）发现了十多个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，可用于改善PSA和其他现有的临床变量，以预测前列腺活检阳性（即PCa）。然而，这两个重要的问题不能通过大多数PCa病例对照研究来解决，因为一些病例是根据PSA水平升高来诊断的。只有像前列腺癌预防试验（PCPT）这样的研究，在试验结束时，不管PSA水平如何，都对男性进行了活组织检查，才能用来剖析这两个问题。该研究的总体假设是，当多种基因变异结合在一起时，可以用来预测患前列腺癌风险增加的男性。具体来说，我们假设1)一部分遗传变异与PCa风险相关，而不仅仅是由于PSA检测偏差；2)这些遗传变异结合起来与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，以提高对PCa和侵袭性PCa的预测性能。4)不同遗传风险男性非那雄胺的化学预防作用不同，遗传风险高的男性非那雄胺对PCa诊断的降低作用更大。为了验证这些假设，我们将使用来自PCPT研究的数据和样本，这是一项非那雄胺预防前列腺癌的随机、双盲、安慰剂对照试验。我们有三个具体目标。目的1是在不存在PSA检测偏倚的情况下，检验GWAS报告的前列腺癌风险相关变异是否与PCa风险相关。目的2是利用遗传变异、PSA和其他现有临床变量，评估前列腺癌诊断、整体前列腺癌和侵袭性前列腺癌的联合预测性能。目的3是评估非那雄胺对前列腺癌遗传风险较高或较低的男性前列腺癌诊断的差异性化学预防作用。这项研究的结果可能会使数百万男性受益。前列腺癌风险最高的男性可以在早期进行密集筛查和化学预防，如非那雄胺。遗传变异也可以与PSA和其他现有的临床变量联合使用，以大大提高其对前列腺活检阳性的预测准确性。公共卫生相关性：几十种前列腺癌风险相关的变异，当结合起来时，可以用来识别前列腺癌风险最高的男性。这样的男性可以在早期被识别出来，进行密集的筛查和化学预防。前列腺癌风险相关变异也可以与PSA和其他现有的临床变量联合使用，以显著提高其对前列腺活检阳性的预测准确性。1

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