Molecular Epidemiology of DNA Repair in Head and Neck Cancer

项目总结/摘要 吸烟、饮酒和遗传易感性是鳞状细胞癌的主要危险因素 头部和颈部（SCCHN）识别易感个体可以有效预防这种疾病， 避免使用烟草和酒精。烟草致癌物可引起靶细胞的多种DNA损伤， 这可能导致细胞生长失控，但细胞进化到具有程序化细胞机制， 死亡或凋亡，有助于消除对DNA过度损伤的细胞，从而降低癌症的风险。 存在至少两种已知的细胞凋亡途径，内源性和外源性，其导致细胞响应于细胞凋亡而死亡。 过度的DNA损伤许多基因参与这两个凋亡途径，并且存在一个已建立的 流式细胞术检测细胞凋亡表型。在这个新的拨款申请中，我们建议执行 在600例新招募的病例和600例对照中进行表型凋亡和基因分型检测， 使用来自先前招募的1，000例SCCHN病例和1，000例 对照对于基因分型，我们建议集中在共同的，可能有功能的单核苷酸 多态性（SNP），其引起调控区中的氨基酸变化或序列变异 这可能会改变基因表达，或者据报道与吸烟相关癌症的风险有关。共有88 将通过Taqman基因分型方法对45个糖尿病相关基因中可能有功能的SNP进行基因分型 使用来自1，600例SCCHN病例（600例前瞻性和1，000例回顾性）和1，600例癌症的基因组DNA， 自由对照（600例前瞻性和1,000例回顾性）。我们的具体目标是：目标1：确定 600例前瞻性确定的淋巴细胞凋亡表型与SCCHN风险之间的相关性 病例和600例医院对照，按年龄、性别、种族/人种和居住地匹配频率。我们将 检验较低水平的凋亡能力与SCCHN风险增加相关的假设。 目的2：在600例正常人中确定凋亡途径中所选常见变异的功能相关性。 通过鉴定预测表型的基因型，对100例患者和600例对照进行研究。我们将检验这个假设， 所选凋亡基因的可能功能性遗传变异体对细胞凋亡有影响， 表型目的3：确定所选基因的常见变异基因型之间的关联性。 糖尿病相关基因与SCCHN风险我们将检验这一假设，即选择的不利基因型 糖尿病相关基因与SCCHN风险增加相关。这项拟议的关联研究是 高度假设驱动，扩大了我们关于新的p53-PHB-PIG 3凋亡发现的初步数据 机制本研究将确定预测SCCHN凋亡表型和风险的遗传因素， 这将进一步加深我们对SCCHN病因学的认识。这项研究的长期目标是确定 用于风险评估的有效生物标志物，并识别可作为主要靶点的高危个体 在一般人群中预防和早期发现SCCHN。项目叙述 本研究旨在探讨遗传因素的作用，以及它们之间的相互作用， 烟草和酒精的使用，口腔、咽和喉鳞状细胞癌的病因学 （SCCHN），扩大了我们以前没有描述过的新的细胞凋亡机制的发现。 因此，本研究将有助于了解细胞凋亡相关性的潜在机制， 待测基因型和表型以及它们在SCCHN病因学中可能发挥的作用。很长的- 这项研究的长期目标是确定有效的生物标志物，可用于识别风险个体， 作为一般人群SCCHN初级预防和早期检测的目标。

Project Summary/Abstract Tobacco and alcohol use and genetic susceptibility are major risk factors for squamous cell carcinoma of the head and neck (SCCHN). Identification of susceptible individuals can effectively prevent this disease by avoiding tobacco and alcohol use. Tobacco carcinogens cause a variety of DNA damage in the target cells, which may lead to uncontrolled cell growth, but the cells evolve to have the mechanism of programmed cell death or apoptosis that helps eliminate cells with excessive damage to DNA and thus reduce risk of cancer. There are at least two known apoptotic pathways, intrinsic and extrinsic, that lead to cell death in response to excessive DNA damage. Many genes participate in these two apoptotic pathways, and there is an established flow cytometry method to detect the apoptosis phenotype. In this new grant application, we propose to perform the phenotypic apoptosis and genotyping assays in 600 newly recruited cases and 600 controls and to perform genotyping assays with stored DNA samples from previously recruited 1,000 SCCHN cases and 1,000 controls. For the genotyping, we propose to focus on the common, possibly functional single nucleotide polymorphisms (SNPs) that either cause amino acid changes or sequence variation in the regulatory regions that may alter gene expression or are reportedly associated with risk of smoking-related cancers. A total of 88 possibly functional SNPs in 45 apoptosis-related genes will be genotyped by the Taqman genotyping method using genomic DNA from 1,600 SCCHN cases (600 prospective and 1,000 retrospective) and 1,600 cancer- free controls (also 600 prospective and 1,000 retrospective). Our specific aims are: AIM 1: To determine the association between the apoptotic phenotype of lymphocytes and risk of SCCHN in 600 prospectively identified cases and 600 hospital-based controls frequency matched by age, sex, ethnicity/race and residence. We will test the hypothesis that lower levels of apoptotic capacity are associated with increased risk of SCCHN. AIM 2: To determine the functional relevance of selected common variants in apoptotic pathways in the 600 cases and 600 controls by identifying genotypes that predict the phenotype. We will test the hypothesis that possibly functional genetic variants of selected apoptotic genes have an effect on the apoptotic phenotype. AIM 3: To determine the association between common variant genotypes of the selected apoptosis-related genes and risk of SCCHN. We will test the hypothesis that adverse genotypes of selected apoptosis-related genes are associated with increased risk of SCCHN. This proposed association study is highly hypothesis-driven, expanding our preliminary data on the findings of a novel p53-PHB-PIG3 apoptosis mechanism. This study will identify genetic factors that predict the apoptotic phenotype and risk of SCCHN and thus will advance our knowledge in the etiology of SCCHN. The long-term goal of this study is to identify effective biomarkers for risk assessment and to identify at-risk individuals who can be targeted for primary prevention and early detection of SCCHN in the general population. Project Narrative This proposed study is to investigate the roles of genetic factors, as well as their interactions with tobacco and alcohol use, in the etiology of squamous cell carcinomas of the oral cavity, pharynx, and larynx (SCCHN), expanding our findings of a novel apoptosis mechanism that has not been described before. Therefore, this study will help understand the underlying mechanisms of the correlation between apoptosis genotypes and phenotypes to be measured and the roles they may play in the etiology of SCCHN. The long- term goal of this study is to identify effective biomarkers that can be used to identify at-risk individuals who will be targeted for primary prevention and early detection of SCCHN in the general population.