Genome-Wide Study to Identify SNPs and CNPs Associated with Radiation Injury

接受近距离放射治疗的前列腺癌患者中的一组经历了辐射损伤 表现为尿路并发症、直肠炎或勃起功能障碍(ED)。结果是从一项 一系列研究提示了临床放射敏感性的遗传基础，并已假设 许多表现出正常组织辐射毒性的患者存在特定的单核苷酸多态。 (SNPs)和拷贝数多态(CnP)与糖尿病易感性相关 前列腺癌放射治疗引起的不良反应。然而，这项研究的目的是 数据仅限于对一小群候选基因中有限数量的SNPs进行基因分型。在……里面 认识到我们对辐射诱发癌症发生的途径了解不足 尿病、直肠炎和勃起功能障碍，以及对基因/蛋白质谱的不完全了解 参与了这些形式的辐射毒性的发展，很可能我们没有识别出许多 与这些辐射损伤表现的发展相关的SNPs和CNP。 因此，我们提出了一种新的创新战略来实现这一目标，在该战略中，全基因组 将进行关联研究，以发现SNPs和CNP(和基因)的更完整的谱 与临床放射敏感性有关。这将是一项病例对照研究，其中每个前列腺癌 出现尿路并发症、直肠炎或勃起功能障碍的患者将在年龄、种族、分期、日期等方面匹配 诊断和剂量学参数，与没有发展为这种形式的适当对照患者 辐射损伤。在这项研究中，每种形式的辐射损伤将有200例病例和200名对照。一半的人 首先将使用Affymetrix 6.0 SNP阵列对受试者进行SNP和CNP筛查。第I类错误(A) 对于拒绝零假设，将设置为0.0001。因此，根据次要等位基因的频率，我们 将能够识别其基因组相对风险(GRR)为每种形式的发育的SNPs和CNP 辐射损伤的风险大于约2.5。尽管这是一个相对较少的数字 全基因组关联研究的对象，因此能够识别SNP或CNP 相对较高的GRR值，重要的是要注意只有GRR值大于约2.5的SNP和CNP才会 考虑到剂量学的不确定性，可能在实际的临床环境中具有有用的预测价值 与标准的放射治疗有关。第二阶段验证研究将通过以下方式进行 包括为该项目选择的受试者的另一半的单独复制集使用a为0.01， 这实际上应该消除了在初始阶段中识别的所有假阳性。最后，我们将表演 对每个SNP周围DNA区域的所有受试者进行全面的SNP筛查，结果为阳性 与受试者复制集中的每种形式的辐射损伤相关联，以便对 单倍型区块。

A subgroup of prostate cancer patients treated with brachytherapy experience radiation-induced injury manifested as either urinary morbidity, proctitis or erectile dysfunction (ED). Results have been obtained from a series of studies suggestive of a genetic basis for clinical radiosensitivity and it has been hypothesized that many patients who exhibit normal tissue radiation toxicity harbor specific single nucleotide polymorphisms (SNPs) and copy number polymorphisms (CNPs) associated with a susceptibility for the development of adverse effects resulting from a radiation treatment for prostate cancer. However, the research performed to date has been restricted to genotyping only a limited number of SNPs in a small group of candidate genes. In recognition of our inadequate understanding of the pathways involved in the development of radiation-induced urinary morbidity, proctitis and ED, as well as the incomplete knowledge of the spectrum of genes/proteins involved in the development of these forms of radiation toxicity, it is likely that we have failed to identify many of the SNPs and CNPs that are associated with the development of these manifestations of radiation injury. Therefore, we are proposing a new and innovative strategy to achieve this goal in which a genome wide association study will be performed to discover a more complete spectrum of the SNPs and CNPs (and genes) that are associated with clinical radiosensitivity. This will be a case-control study in which each prostate cancer patient that develops either urinary morbidity, proctitis or ED will be matched on age, race, stage, date of diagnosis and dosimetric parameters, with an appropriate control patient who did not develop that form of radiation injury. There will be 200 cases and 200 controls for each form of radiation injury in this study. Half of the subjects will first be screened for SNPs and CNPs using the Affymetrix 6.0 SNP array. The type I error (a) for rejection of the null hypothesis will be set at 0.0001. Therefore, depending on the minor allele frequency, we will be able to identify SNPs and CNPs whose genome relative risks (GRRs) for the development of each form of radiation induced injury is greater than approximately 2.5. Although this is a relatively modest number of subjects for a genome wide association study, therefore enabling identification of SNPs or CNPs only with relatively high GRRs, it is important to note that only SNPs and CNPs with GRRs greater than roughly 2.5 will likely be of useful predictive value in the actual clinical setting considering the dosimetric uncertainties associated with a standard radiotherapy treatment. A second phase validation study will be performed with a separate replication set comprising the other half of the subjects selected for this project using an a of 0.01, which should eliminate virtually all false positives identified in the initial phase. Finally, we will perform comprehensive SNP screening for all subjects of the DNA region surrounding every SNP that proves positively associated with each form of radiation injury in the replication set of subjects in order to genotype all SNPs in a haplotype block.