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

我们的目标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：一个病例对照研究，以确定与SCCHN风险相关的单核苷酸多态性（SNP）（目标1），一个患者队列研究，以确定与无进展生存期（PFS）（目标2）和治疗反应（目标3）相关的SNP，重点是铂类药物治疗。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，并提供了病例的详细临床、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，为我们提供了开展这些研究的独特能力。DNA修复途径基因与SCCHN风险和治疗反应有关。我们目前SPORE研究的初步数据与最近其他报告一致，这些报告显示，由核苷酸切除修复（NER）介导的DNA修复能力降低可能与铂类治疗病例的PFS相关。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，包括NER途径的所有基因成员。在初步的单倍型关联分析中，我们已经确定了几个基因单倍型与铂类治疗病例的PFS增加或减少相关。作为这种假设驱动的候选基因方法的补充，全基因组关联研究（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面板，通过实施一个混合策略SNP选择纳入候选DNA修复途径和细胞周期基因和非候选基因的方法的基础上正在进行的I期GWAS研究的新兴数据。这种应用于大样本量遗传变异选择的综合方法提供了鉴定和表征易感性、预后和预测治疗反应的新型遗传生物标志物的机会。我们将使用基于SNP和单倍型的方法来评估遗传因素的作用及其与环境在SCCHN风险和疾病结局中的相互作用。

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.