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

我们建议进行一个遗传流行病学单倍型关联项目，评估多态。 在一系列非小细胞肺癌病例和对照中，研究了NER和细胞周期控制通路中的基因。有能力 确定与烟草相关的癌症风险最高的个人，最重要的是肺癌， 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，还有一个非常强的 也研究吸烟引起的DNA损伤修复能力的变异性的生物学基础 另一个主要的易感生物标志物家族。核苷酸切除修复(NER)途径是重要的 在修复化学致癌物引起的遗传毒性损伤方面。XPD蛋白是这个过程中的一个关键成员 XPD基因的途径和突变，包括常见的A35931C(Lys751Gln)变异等位基因，结果 维修能力下降。此外，细胞周期调控机制的调节可以影响 增加细胞增殖和促进遗传不稳定的可能性。细胞周期蛋白D_1(CCND_1)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。我们的 最初的病例/对照研究表明，上皮性心脏病的风险增加与 同时携带CCND1870A变异等位基因和XPD基因的个体中的呼吸消化道癌 等位基因(OR=7.1，95%CI 4.0~12.5)。我们建议将这些观察扩展到包括通路单倍型 关联性分析，重点分析与NER通路和5个关键细胞周期有关的所有25个基因 控制基因，以便捕获两个中所选基因内的所有常见遗传变异 并评估这种变异是如何导致肺癌风险的。来检验预测结果 这些单倍型的意义，我们还将通过对PLuSS和PLuSS进行基因分型进行前瞻性研究 莫菲特癌症中心的高危子队列。我们还将开发最终的预测模型，将 来自病例/对照和特定目标2和3的预期研究的数据集 验证。NER基因单倍型不仅可以预测肺癌风险，而且还可以预测耐药和 生死存亡。众所周知，对铂类药物的耐药性是一种经常用于 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。这种基于单倍型的方法 将提供大量关于基因和途径的信息，并将有助于评估基因如何 变异与肺癌风险有关。能够快速筛查个人的风险和预后，使用 非侵入性手术，在未来的临床应用中具有巨大的潜力。

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.