Exploring the Association Between Immune-Related Genetic Variation and HNSCC

描述(申请人提供)：头颈部鳞状细胞癌(HNSCC)是全球第六大常见癌症，每年新诊断病例超过50万例。虽然大多数HNSCC病例与接触烟草和酒精或感染人乳头状瘤病毒(HPV)有关，但大多数暴露于HNSCC的人不会患癌症，这表明基因变异在易感性中发挥了作用。由免疫相关基因的变异性决定的宿主的免疫状态，可能是接触者癌症进展风险的一个修饰物。基因工程小鼠为实体瘤模型中的癌症免疫监控提供了证据。与野生型小鼠相比，免疫缺陷小鼠肿瘤发生的频率更高。同样，免疫抑制的患者患鳞癌的风险也增加了。HPV诱导的口咽癌(OPC)似乎与免疫相关基因的变异密切相关，因为HPV感染是致癌的必要条件，但不是充分条件。因此，HNSCC是分析免疫基因调控实体瘤易感性的理想模型系统。通常，研究HNSCC风险的遗传决定因素的研究只检查几个单核苷酸多态(SNPs)，并集中在致癌物代谢和DNA修复基因的变异上。这些研究的局限性包括：检测适度风险序列变异的统计能力低、假阳性结果、阳性发表偏倚、以及每个SNP单独导致风险大幅增加的适度先验概率。为了克服这些问题，我们将把一种新的分析策略应用于国际头颈癌流行病学联合会进行的基因组广泛关联研究(GWAS)，使用假设驱动的多候选基因方法，并整合用于数据质量控制、候选基因排名和路径分析的改进方法。我们认为宿主免疫相关基因的遗传变异与HNSCC易感性改变有关。这一建议的目的是：1)探索免疫相关基因的遗传变异与HNSCC易感性之间的关系，并寻找与HNSCC发病风险增加相关的候选免疫相关基因。我们将利用GWAS的数据，评估候选基因中的变异与HNSCC风险之间的关联，并进行基于途径的SNP关联分析，以揭示复杂的免疫遗传学与HNSCC风险的关联。我们还将对HPV诱导的OPC患者进行单独的SNP关联分析，使用修改后的候选免疫相关基因列表，包括与癌症和病毒易感性以及宿主反应相关的基因。2)通过对基因组DNA进行复制研究，在独立的HNSCC病例和对照队列中验证排名较高的免疫相关基因。

DESCRIPTION (provided by applicant): Head and neck squamous cell carcinoma (HNSCC) is the sixth most frequent cancer worldwide with over 500,000 new cases diagnosed yearly. While most HNSCC cases are associated with exposure to tobacco and alcohol or infection with the human papilloma virus (HPV), the majority of persons exposed do not develop cancer, suggesting genetic variation plays a role in susceptibility. A potential modifier of risk of progression to cancer in those exposed is the immune status of the host as determined by variability of immune-related genes. Genetically engineered mice have provided evidence for cancer immunosurveillance in solid tumor models. Immunodeficient mice have shown an increased frequency of tumor development compared to wild-type mice. Likewise, immunosuppressed patients also have an increased risk for developing SCC. HPV-induced Oropharyngeal Cancer (OPC) appears intimately related to variants in immune- related genes because HPV infection is necessary but not sufficient for carcinogenisis. Thus, HNSCC is an ideal model system for the analysis of immune genes modulating susceptibility to solid tumors. Typically, studies investigating the genetic determinants of risk of HNSCC examine only several single nucleotide polymorphisms (SNPs) and focus on variants in carcinogen metabolism and DNA repair genes. Limitations in these studies include low statistical power in detecting modest risk sequence variants, false positive results, positive publication bias, and a moderate prior probability that each SNP individually confers substantial increase in risk. To overcome these issues we will apply a novel strategy of analysis to the Genome Wide Association Study (GWAS) performed by the International Head and Neck Cancer Epidemiology Consortium using a hypothesis-driven multi-candidate gene approach and integrating improved methods for data quality control , candidate gene ranking and pathway analysis. We propose that genetic variations in host immune-related genes are associated with altered susceptibility to HNSCC. The aims of this proposal are: 1) Explore the association between genetic variations in immune-related genes and susceptibility to HNSCC and identify candidate immune-related genes associated with increased risk of developing HNSCC. Using data from the GWAS, we will evaluate the association between variants in the candidate genes and risk of HNSCC and perform a pathway based SNP association analysis to uncover complex immunogenetic associations to the risk of HNSCC. We will also perform a separate SNP association analysis of patients with HPV-induced OPC using a modified candidate immune-related genes list including genes related to both cancer and viral susceptibility and host response. 2) Validate highly ranked immune-related genes in an independent cohort of HNSCC cases and controls by performing replication studies using PCR analysis of genomic DNA.