Prospective Study of DNA Repair Gene Variants in Breast Cancer

描述（由申请人提供）：乳腺癌中DNA修复基因变异的前瞻性研究我们建议在护士健康研究（NHS）中的一项大型巢式病例对照研究中前瞻性评估DNA修复和相关基因的遗传多态性与乳腺癌风险，该研究包括2096例病理证实的乳腺癌病例和2979例匹配对照。具体而言，我们将全面系统地评估五种DNA修复途径的遗传变异，包括碱基切除修复，核苷酸切除修复，双链断裂修复（DNA损伤反应，同源重组和非同源末端连接），直接逆转修复和错配修复，沿着候选DNA聚合酶和范可尼贫血互补组。我们将使用两种互补方法调查每个位点的常见遗传变异：1）评估非同义多态性，2）使用高密度基因分型数据选择tag-SNP，以检测未知功能相关区域中常见变异与乳腺癌风险的关联。我们将评估在诊断前收集的血浆样本中测量的变体与叶酸状态和抗氧化剂状态（主要是α-和β-胡萝卜素）之间的先验假设相互作用对乳腺癌风险的影响。我们将有很大的能力来检测大多数感兴趣的基因型的主要影响以及基因型和生物标志物之间的相互作用。我们的研究将通过更详细地评估DNA修复基因中常见变异在乳腺癌病因学中的作用，大大增加证据。涉及DNA修复途径遗传多态性的基因-环境相互作用分析可能为暴露对乳腺癌风险的遗传毒性效应提供新的见解。现有NHS队列的几个独特特征包括队列特征、设计质量、大样本量、前瞻性暴露评估的严格性、高应答率和随访率以及存档的生物标本。这项创新工作对于推进这一领域至关重要，并且它具有应用于其他癌症易感性领域的巨大潜力。

DESCRIPTION (provided by applicant): Prospective Study of DNA Repair Gene Variants in Breast Cancer We propose to prospectively evaluate inherited polymorphisms in DNA repair and related genes with breast cancer risk in a large nested case-control study within the Nurses' Health Study (NHS) with 2096 pathologically confirmed incident breast cancer cases and 2979 matched controls. Specifically, we will comprehensively and systematically evaluate genetic variation in five DNA repair pathways, including base excision repair, nucleotide excision repair, double strand break repair (DNA damage response, homologous recombination and non-homologous end-joining), direct reversal repair, and mismatch repair, along with candidate DNA polymerases and Fanconi Anemia complementation groups. We will survey common genetic variation at each locus using two complementary approaches; 1) to evaluate nonsynonymous polymorphisms and 2) to choose tag-SNPs using high-density genotyping data to test for the association of common variants in regions of unknown functional relevance with breast cancer risk. We will evaluate a priori hypothesized interactions between the variants and folate status and antioxidant status (primarily a- and p- carotenes), as measured in pre-diagnostically collected plasma samples, on breast cancer risk. We will have substantial power to detect the main effects of most of the genotypes of interest and interactions between the genotypes and the biomarkers. Our study will add substantially to the body of evidence by evaluating in considerably more detail the roles of common variants in DNA repair genes in breast cancer etiology. Gene- environment interaction analysis involving genetic polymorphisms in DNA repair pathways may provide new insights into the genotoxic effects of exposures on breast cancer risk. Several unique features of the existing NHS cohort include cohort characteristics, quality of design, large sample size, rigor in prospective exposure assessment, high response and follow-up rates, and archived bio-specimens. This innovative work is essential to advance this field, and it has substantial potential for application to other areas of cancer susceptibility.