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

描述（由申请人提供）：吸烟和饮酒以及遗传易感性是头颈部鳞状细胞癌（SCCHN）的主要危险因素。识别易受感染的个人可以有效地帮助预防这种疾病，避免吸烟和饮酒。烟草致癌物在靶细胞中引起多种DNA损伤，可能导致细胞生长失控，但细胞进化具有程序性细胞死亡（凋亡）机制，有助于消除DNA损伤过度的细胞，从而降低癌症风险。至少有两种已知的细胞凋亡途径，内在和外在的，导致细胞死亡，响应于过度的DNA损伤，并有一个既定的流式细胞术方法来检测细胞凋亡表型。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型分析，并对另外1，000名SCCHN患者和1，000名对照受试者进行基因型分析，并使用之前获得的存储DNA样本。共选择了50个糖尿病相关基因的434个常见SNP（包括88个pupirus-functional和346个tagging），并将使用SNPs基因分型方法对所有3，200例受试者（1，600例病例和1，600例对照）进行基因分型。我们的具体目标是：目的1：确定434个常见SNP之间的关联（即，次要等位基因频率e0.05）基因型与SCCHN的风险。我们还将检测前瞻性招募的480例SCCHN患者的TP 53突变和HPV感染，旨在确定本研究人群中最易感的亚组。目的2：确定细胞凋亡表型与SCCHN风险之间的关系。目标3：通过鉴定预测表型的基因型，确定所选常见标签SNP在凋亡途径中的功能相关性。我们还将使用来自所有1，600例病例和1，600例对照的基因分型数据以及描述每个人吸烟史的问卷数据来探索基因-基因和基因-环境相互作用，并确定本研究人群中最易感的亚组。这项相关性研究是高度假设驱动的，扩展了我们关于新的p53-PHB-PIG 3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，从而提高我们对SCCHN病因学的认识。这项研究的长期目标是确定有效的生物标志物进行风险评估，并确定在一般人群中可以作为SCCHN一级预防和早期检测目标的高危人群。

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.