Pathway and GWAS SNPs: Role in SCCHN Risk, Outcome and Treatment Response

通路和 GWAS SNP：在 SCCHN 风险、结果和治疗反应中的作用

• 批准号: 8541585
• 负责人: BRENDA DIERGAARDE
• 金额: $ 33.01万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8541585
• 关键词: Address; Age; Alcohol consumption; Alcohols; Biological; CCND1 gene; Cancer Etiology; Candidate Disease Gene; Carcinogens; Case-Control Studies; Cell Cycle; Cell Cycle Regulation; Cessation of life; Chemoprevention; Clinic; Clinical; Cohort Studies; Complex; Custom; DNA Repair; DNA Repair Gene; DNA Repair Pathway; Data; Demographic Factors; Detection; Disease; Disease Outcome; Disease Progression; ERCC2 gene; Early Diagnosis; Environment; Environmental Exposure; Ethanol Metabolism; Etiology; Evaluation; Excision Repair; Frequencies; Funding; Future; Gender; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Genotype; Haplotypes; Head and Neck Squamous Cell Carcinoma; Human Papillomavirus; Hybrids; Intervention; Lead; Malignant Neoplasms; Measures; Mediating; Modeling; Modification; Nucleotide Excision Repair; Outcome; Pathologic; Pathway interactions; Patients; Penetrance; Phase; Platinum; Predisposition; Prevention; Prognostic Marker; Progression-Free Survivals; Public Health; Race; Recording of previous events; Reporting; Research Design; Resources; Risk; Risk Factors; Role; S Phase; Sample Size; Single Nucleotide Polymorphism; Site; Smoking; Specialized Program of Research Excellence; Staging; Subgroup; Susceptibility Gene; Testing; Therapeutic; Tobacco; Tobacco use; Update; base; cdc Genes; chemotherapeutic agent; chemotherapy; cytotoxic; design; genetic association; genetic risk factor; genetic selection; genetic variant; genome wide association study; high risk; member; non-smoker; novel; outcome forecast; repaired; response; sample collection; screening; treatment response; tumor

Our objective is to identify genetic modulators of risk, prognosis and response to therapy for squamous cell carcinoma of the head and neck (SCCHN). We will employ two basic study designs to achieve three aims: a case control study to identify single nucleotide polymorphisms (SNPs) associated with SCCHN risk (Aim 1), and a patient cohort study to identify SNPs associated with progression free survival (PFS)(Aim 2) and treatment response (Aim 3), with a focus on platinum-based therapy. Our large specimen collection with over 1000 controls and 750 SCCHN cases to date with detailed clinical, pathologic and survival data for cases and demographic and risk factor data for all subjects provides us the unique ability to carry out these studies. DNA repair pathway genes have been implicated in both SCCHN risk and response to therapy. Preliminary data from our current SPORE study are consistent with other recent reports that show reduced DNA repair capacity, mediated by nucelotide excision repair (NER), may be associated with PFS in platinum-treated cases. We have recently expanded our genotyping analysis to a comprehensive 384 single nucleotide polymorphism (SNP) panel that includes all of the gene members of the NER pathway. In a preliminary haplotype association analysis, we have identified several gene haplotypes associated with either enhanced or reduced PFS in platinum-treated cases. Complementary to this hypothesis-driven candidate gene approach, genome wide association studies (GWAS) can identify new susceptibility genes without making a priori biological assumptions. We plan to design a 1536 SNP panel by implementing a hybrid strategy for SNP selection incorporating both candidate DNA repair pathway and cell cycle genes and a noncandidate gene approach based on emerging data from ongoing phase I GWAS studies. This integrated approach applied toward the selection of genetic variants in a large sample size provides the opportunity to identify and characterize novel genetic biomarkers of susceptibility, prognosis and prediction of therapeutic response. We will use SNP- and haplotype-based approaches in our evaluation of the role of genetic factors and their interactions with the environment in SCCHN risk and disease outcome.

我们的目的是确定头颈部鳞状细胞癌（SCCHN）的风险、预后和治疗反应的遗传调节因子。我们将采用两种基本研究设计来实现三个目标：一种是病例对照研究，确定与SCCHN风险相关的单核苷酸多态性（snp）（Aim 1）；另一种是患者队列研究，确定与无进展生存（PFS）（Aim 2）和治疗反应（Aim 3）相关的snp，重点是铂基治疗。迄今为止，我们收集了超过1000例对照和750例SCCHN病例的大量标本，详细的临床、病理和生存数据，以及所有受试者的人口统计学和风险因素数据，为我们开展这些研究提供了独特的能力。DNA修复途径基因与SCCHN风险和对治疗的反应都有关系。我们目前SPORE研究的初步数据与其他最近的报道一致，表明在铂治疗病例中，由核苷酸切除修复（NER）介导的DNA修复能力降低可能与PFS有关。我们最近将我们的基因分型分析扩展到一个全面的384个单核苷酸多态性（SNP）面板，其中包括NER通路的所有基因成员。在初步的单倍型关联分析中，我们已经确定了几种与铂治疗病例PFS增强或降低相关的基因单倍型。作为这种假设驱动的候选基因方法的补充，基因组全关联研究（GWAS）可以在不进行先验生物学假设的情况下识别新的易感基因。我们计划设计一个1536 SNP小组，通过实施混合策略进行SNP选择，结合候选DNA修复途径和细胞周期基因，以及基于正在进行的I期GWAS研究的新数据的非候选基因方法。这种综合方法应用于大样本量遗传变异的选择，为鉴定和表征易感性、预后和治疗反应预测的新型遗传生物标志物提供了机会。我们将使用基于SNP和单倍型的方法来评估遗传因素及其与环境的相互作用在SCCHN风险和疾病结局中的作用。