Genotypes and Phenotypes of Apoptosis and Risk of Head and Neck Cancer

描述(申请人提供)：烟酒使用和遗传易感性是头颈部鳞状细胞癌(SCCHN)的主要危险因素。识别易感人群可以通过避免使用烟草和酒精有效地促进预防这种疾病。烟草致癌物对靶细胞造成多种DNA损伤，可能导致细胞生长失控，但细胞进化具有细胞程序性死亡(细胞凋亡)的机制，有助于消除DNA过度损伤的细胞，从而降低癌症风险。至少有两条已知的凋亡途径，即内在和外在途径，导致细胞在过度DNA损伤时死亡，并且有一种成熟的流式细胞术方法来检测细胞的凋亡表型。在这项新的拨款申请中，我们建议对600名新招募的SCCHN患者和600名对照受试者进行细胞凋亡表型和基因分型分析，并利用先前获取的储存DNA样本对另外1,000名SCCHN患者和1,000名对照受试者进行基因分型分析。共选择了50个凋亡相关基因的434个常见SNPs(包括88个推测功能基因和346个标签基因)，并将使用SNPlex基因分型方法对所有3,200名受试者(1,600例患者和1,600名对照)进行基因分型。我们的具体目标是：目标1：确定50个选定的凋亡相关基因的434个常见SNPs(即次要等位基因频率e 0.05)与SCCHN风险的相关性。我们还将检测480名SCCHN患者的TP53突变和HPV感染情况，旨在确定该研究人群中最敏感的亚组。目的2：探讨细胞凋亡表型与SCCHN发病风险之间的关系。目的3：通过鉴定预测表型的基因类型，确定选定的常见标签SNPs在细胞凋亡途径中的功能相关性。我们还将使用所有1600名病例和1600名对照的基因分型数据和问卷数据来探索基因-基因和基因-环境的相互作用，这些数据描述了每个人的吸烟史，并确定了研究人群中最易受影响的亚群。这项拟议的相关性研究是高度假设驱动的，扩大了我们关于一种新的p53-PHB-PIG3凋亡机制的初步数据。这项研究将确定预测SCCHN的凋亡表型和风险的遗传因素，从而促进我们对SCCHN病因的认识。这项研究的长期目标是确定用于风险评估的有效生物标记物，并确定可作为普通人群SCCHN初级预防和早期检测的高危个体。公共卫生相关性：这项拟议的研究的目的是调查遗传因素以及它们与烟草和酒精使用以及P53突变和HPV感染的相互作用在口腔、咽和喉鳞状细胞癌(SCCHN)的病因学中的作用，扩大我们对一种以前从未描述过的新的细胞凋亡机制的发现。因此，本研究将有助于我们了解凋亡基因与待检测表型之间相关性的潜在机制，以及它们在SCCHN发病机制中可能发挥的作用。这项研究的长期目标是确定有效的生物标志物，可用于识别普通人群中将成为SCCHN初级预防和早期发现目标的高危个体。

DESCRIPTION (provided by applicant): 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 facilitate prevention of 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 (apoptosis), which helps eliminate cells with excessive DNA damage and thus reduce cancer risk. At least two known apoptotic pathways, the intrinsic and extrinsic, lead to cell death in response to excessive DNA damage, and there is an established flow-cytometry method to detect the apoptosis phenotype. In this new grant application, we propose to perform apoptosis phenotyping and genotyping assays in 600 newly recruited patients with SCCHN and 600 control subjects and to perform genotyping assays for an additional 1,000 SCCHN patients and 1,000 control subjects with stored DNA samples procured previously. A total of 434 common (including 88 putatively functional and 346 tagging) SNPs of 50 apoptosis-related genes have been selected and will be genotyped by using the SNPlex genotyping method for all 3,200 subjects (1,600 cases and 1,600 controls). Our specific aims are: AIM 1: To determine the association between 434 common SNPs (i.e., minor allele frequency e 0.05) genotypes of 50 selected apoptosis-related genes and the risk of SCCHN. We will also detect TP53 mutations and HPV infection of a subset of 480 SCCHN patients to be prospectively recruited, aiming at identifying the most susceptible subgroups in this study population. AIM 2: To determine the association between the apoptotic phenotype and the risk of SCCHN. AIM 3: To determine the functional relevance of selected common tagging SNPs in apoptotic pathways by identifying the genotypes that predict the phenotypes. We will also explore the gene-gene and gene-environment interactions using the genotyping data from all 1,600 cases and 1,600 controls and questionnaire data that characterized the smoking history of each individual and identify the most susceptible subgroups in this study population. 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 of 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. PUBLIC HEALTH RELEVANCE: The purpose of this proposed study is to investigate the roles of genetic factors, as well as their interactions with tobacco and alcohol use as well as p53 mutations and HPV infections, 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 us 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 in the general population who will be targeted for primary prevention and early detection of SCCHN.