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

前列腺癌患者接受近距离放射治疗后出现放射性损伤 表现为泌尿系统疾病、直肠炎或勃起功能障碍（艾德）。结果已经从一个 一系列研究表明临床放射敏感性的遗传基础，并假设 许多表现出正常组织辐射毒性的患者具有特定的单核苷酸多态性 （SNPs）和拷贝数多态性（CNP）与发展的易感性相关。 前列腺癌放射治疗引起的副作用。然而，研究表明， 迄今为止仅限于对一小组候选基因中有限数量的SNP进行基因分型。在 认识到我们对辐射引起的疾病发展所涉及的途径认识不足， 泌尿系统疾病、直肠炎和艾德，以及对基因/蛋白质谱的不完全了解 参与发展这些形式的辐射毒性，很可能我们没有确定许多 SNPs和CNPs与辐射损伤的这些表现的发展相关。 因此，我们提出了一个新的和创新的战略，以实现这一目标， 将进行关联研究，以发现SNP和CNP（和基因）的更完整谱 与临床放射敏感性相关的基因。这将是一项病例对照研究，其中每种前列腺癌 发生泌尿系统疾病、直肠炎或艾德的患者将在年龄、种族、分期、 诊断和剂量测定参数，与适当的对照患者谁没有发展的形式， 辐射损伤本研究中每种形式的辐射损伤将有200例病例和200例对照。半年 首先使用Affysse6.0 SNP阵列筛选受试者的SNP和CNP。第一类错误（a） 零假设的拒绝将被设置为0.0001。因此，根据次要等位基因频率，我们 将能够识别SNP和CNP，其基因组相对风险（GRR）为每种形式的发展 辐射损伤的概率大于2.5。虽然这是一个相对温和的数字， 用于全基因组关联研究的受试者，因此能够仅用 虽然GRR相对较高，但重要的是要注意，只有GRR大于约2.5的SNP和CNP才会 考虑到剂量测定的不确定性，在实际临床环境中可能具有有用的预测价值 与标准放射治疗相关。第二阶段验证研究将使用 单独的重复组包括使用0.01的a为该项目选择的另一半受试者， 这实际上应该消除在初始阶段识别的所有假阳性。最后，我们将表演 对所有受试者的DNA区域周围的每个SNP进行全面的SNP筛查，以证明阳性 与受试者的复制组中的每种形式的辐射损伤相关，以便对受试者的复制组中的所有SNP进行基因分型。 单倍型区组

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.