NUCLEOTIDE EXCISION REPAIR/CELL CYCLE CONTROL HAPLOTYES AND LUNG CANCER RISK AND

我们建议进行遗传流行病学单倍型关联项目评估多态性 一系列NSCLC病例和对照中NER和细胞周期控制途径的基因。的能力 确定患烟草相关癌症（最重要的是肺癌）风险最高的个体， 对筛查、早期发现、预防和治疗具有重要的公共卫生和临床意义。 除了诱变剂的激活和解毒途径的可变性外， 生物学原理也研究了修复吸烟引起的DNA损伤的能力的变化， 另一个主要的易感性生物标志物家族。核苷酸切除修复（NER）途径是重要的 修复化学致癌物引起的遗传毒性损伤。XPD蛋白质是其中的关键成员， 途径和XPD基因突变，包括常见的A35931 C（Lys 751 Gln）变异等位基因，导致 降低修复能力。此外，细胞周期控制机制的调节可以影响细胞周期。 增加细胞增殖和促进遗传不稳定性的潜力。细胞周期蛋白D1（CCND 1）是一种 是一种重要的细胞周期调节蛋白，参与细胞增殖和分化的调节。我们 最初的病例/对照研究已经证明， 同时携带CCND 1 870 A变异等位基因和XPD Gin的个体中的呼吸消化道癌 等位基因（OR=7.1，95%CI 4.0-12.5）。我们建议扩展这些观察，包括一个途径单倍型 关联分析，集中在NER途径和5个关键细胞周期中涉及的所有25个基因 控制基因，以捕获两个基因中所选基因内的所有共同遗传变异。 研究人员发现，这些变异可能会导致肺癌的风险。为了测试预测 这些单倍型的重要性，我们还将进行一项前瞻性研究，通过基因分型PLuSS和 Moffitt癌症中心高风险子队列。我们还将通过结合 特定目的2和3中病例/对照和前瞻性研究的数据集，用于外部 验证。NER基因单倍型不仅可以预测肺癌的风险，还可以预测耐药性， 生存众所周知，对铂类药物（一种常用于化疗的化疗方案）的耐药性是导致肿瘤复发的主要原因。 肺癌的治疗与NER蛋白的上调有关。为了进一步评估 单倍型/表型关系，我们建议研究NER单倍型与 肺癌患者对铂类药物治疗的反应。这种基于单体型的方法 将提供大量关于基因和途径的信息，并将有助于评估基因是如何遗传的。 变异与肺癌风险有关。使用快速筛查个体风险和预后的能力， 非侵入性手术，具有巨大的未来临床应用潜力。

We propose to conduct a genetic epidemiology haplotype association project evaluating polymorphisms of genes in the NER and cell cycle control pathways in a series of NSCLC cases and controls. The ability to identify individuals with the highest risk of developing tobacco-related cancers, most importantly lung cancer, has important public health and clinical implications for screening, early detection, prevention and treatment. In addition to variability in activation and detoxification pathways of mutagenic agents, there is a very strong biologic rationale to also study the variability in the capacity to repair smoking induced DNA damage as another major family of susceptibility biomarkers. The nucleotide excision repair (NER) pathway is important in the repair of chemical carcinogen induced genotoxic damage. The XPD protein is a key member of this pathway and mutations in the XPD gene, including the common A35931C (Lys751Gln) variant allele, result in reduced repair capacity. Furthermore, regulation of the cell cycle control mechanism can influence the potential for increased cell proliferation and the promotion of genetic instability. Cyclin D1 (CCND1) is an essential cell cycle regulatory protein and is involved in the regulation of proliferation and differentiation. Our initial case/control studies have demonstrated a significant association between elevated risk of upper aerodigestive tract cancer among individuals who carried both the CCND1 870A variant allele and XPD Gin allele (OR=7.1, 95%CI 4.0-12.5). We propose to extend these observations to include a pathway haplotype association analysis, focusing on all of the 25 genes involved in the NER pathway and 5 key cell cycle control genes, in order to capture all of the common genetic variation within the selected genes in the two pathways of interest and evaluate how this variation contributes to lung cancer risk. To test the prognostic significance of these haplotypes, we will also perform a prospective study by genotyping the PLuSS and Moffitt Cancer Center High-Risk sub-cohorts. We will also develop a final predictive model by combining the datasets from the case/control and prospective studies in Specific Aims 2 and 3 for purposes of external validation. The NER gene haplotypes may not only predict lung cancer risk, but also drug resistance and survival. It is well known that resistance to platinum-based drugs, a chemotherapeutic regimen often used in the treatment of lung cancer, is associated with up-regulation of NER proteins. In order to further evaluate the haplotype/phenotype relationship, we propose to study the relationship of the NER haplotype with response to platinum-based drug treatment among the lung cancer cases. This haplotype-based approach will provide a great amount of information about genes and pathways and will help to evaluate how genetic variation relates to lung cancer risk. The ability to rapidly screen individuals for risk and prognosis, using non-invasive procedures, has tremendous potential for future clinical application.