CYCLIN D1 & XPD POLYMORPHISMS AS RISK FACTORS OF SCCHN

描述（由申请人提供）：我们的目标是解决基本问题 关于遗传背景调节人类对头颈部鳞状细胞癌（SCCHN）易感性的程度。烟草致癌物质代谢的个体间和种族间差异被认为是疾病易感性变化的主要贡献者。除了诱变剂的激活和解毒途径的变异性之外，修复吸烟诱导的DNA损伤的能力的变异性可能代表另一个主要的易感性生物标志物家族。核苷酸切除修复（NER）系统在化学致癌物诱导的遗传毒性损伤修复中起重要作用。XPD蛋白是该途径的关键成员，XPD基因中的突变，包括常见的A35931 C（Lys 751 Gln）变体等位基因，导致修复能力降低。细胞周期蛋白D1（Cyclin D1，CCND 1）是一种重要的细胞周期调控蛋白，参与细胞增殖和分化的调控。据报道，CCND 1 G870 A多态性可增强选择性剪接并增加细胞周期蛋白D1蛋白半衰期;因此，具有该变体等位基因的受试者可能对细胞增殖增加的易感性增加，并通过绕过细胞周期控制机制的G1/S检查点而促进遗传不稳定性。我们建议评估XPD和CCND 1基因多态性对HNSCC易感性的影响，以进一步完善吸烟和/或饮酒个体的HNSCC风险评估模型。我们计划扩展我们对同时携带CCND 1870 A变异等位基因和XPD Gln等位基因的个体中上呼吸消化道癌风险升高之间的关联的初步观察（10.4，95%CI 5.3-20.4）。在具体目标1中，我们将在一系列匹配的SCCHN病例（N=750）和对照组（N=1000）中验证这些结果。具体目标2将评估这些CCND 1和/或XPD基因多态性是否与第二原发性肿瘤复发或发展的风险升高相关。在具体目标3中，我们提出确定外周血单核细胞（PBMC）中CCND 1和XPD多态性与SCCHN组织中遗传改变之间的相关性。

DESCRIPTION (provided by applicant): Our objective is to address the fundamental question concerning the extent to which genetic background modulates human susceptibility to head and neck squamous cell carcinoma (SCCHN). Interindividual and interethnic differences in tobacco carcinogen metabolism are considered to be major contributors to variations observed in disease susceptibility. In addition to variability in activation and detoxification pathways of mutagenic agents, variability in the capacity to repair smoking induced DNA damage is likely to represent another major family of susceptibility biomarkers. The nucleotide excision repair (NER) system 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 (Lys751 Gln) variant allele result in reduced repair capacity. Cyclin D1 (CCND1) is an essential cell cycle regulatory protein and is involved in the regulation of proliferation and differentiation. The CCND1 G870A polymorphism has been reported to enhance alternate splicing and increase cyclin D1 protein half-life; consequently subjects with the variant allele may have increased susceptibility to increased cell proliferation and the promotion of genetic instability by the bypass of the G1/S checkpoint of the cell cycle control mechanism. We propose to assess the effect of genetic polymorphisms in the XPD and CCND1 genes on susceptibility to HNSCC in order to further refine the HNSCC risk assessment model for individuals with smoking and/or alcohol consumption. We plan to extend our initial observations of an association between elevated risk of upper aerodigestive tract cancer among individuals who carried both the CCND1870A variant allele and XPD Gln allele (10.4, 95%CI 5.3-20.4). In specific aim 1, we will validate these results in a series of matched SCCHN cases (N=750) and controls (N=1000). Specific aim 2 will evaluate whether these CCND1 and/or XPD genetic polymorphisms are associated with elevated risk of recurrence or development of a second primary tumor. In specific aim 3, we propose to determine the correlation between CCND1 and XPD polymorphisms in peripheral blood mononuclear cells (PBMC) and, genetic alterations in SCCHN tissues.