Exploring the Association Between Immune-Related Genetic Variation and HNSCC

探索免疫相关基因变异与 HNSCC 之间的关联

• 批准号: 8256320
• 负责人: Chaya Levovitz
• 金额: $ 3.67万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8256320
• 关键词: Accounting; Alcohols; B-Lymphocytes; Behavioral; Biological Models; Candidate Disease Gene; Carcinogen Metabolism; Carcinogens; Complex; Cutaneous; DNA; DNA Repair; Data; Data Quality; Development; Diagnosis; Disease; Early Diagnosis; Environmental Carcinogens; Epithelial; Exposure to; Frequencies; Genes; Genetic Determinism; Genetic Markers; Genetic Variation; Genetically Engineered Mouse; Genomics; Genotype; HIV; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Human Papillomavirus; Human papilloma virus infection; Immune; Immune response; Immune system; Immunocompromised Host; Immunodeficient Mouse; Immunogenetics; Immunologic Monitoring; Immunosuppression; Immunotherapeutic agent; Incidence; Infection; Interferons; International; Intervention; Malignant Neoplasms; Methods; Natural Killer Cells; Pathway Analysis; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Phase; Play; Population; Populations at Risk; Predisposition; Probability; Publication Bias; Quality Control; Risk; Risk Assessment; Role; Series; Signal Transduction; Single Nucleotide Polymorphism; Site; Solid Neoplasm; Survival Rate; Susceptibility Gene; Systems Analysis; T-Lymphocyte; Testing; Tobacco; Transplant Recipients; Variant; Viral Cancer; alcohol exposure; base; cancer epidemiology; cancer risk; carcinogenesis; case control; cohort; design; disorder control; genetic risk factor; genome wide association study; genome-wide; improved; malignant oropharynx neoplasm; mouse model; novel; novel strategies; sarcoma; tobacco exposure; tumor

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 yearly1. 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 genes2. Genetically engineered mice have provided evidence for cancer immunosurveillance in solid tumor models5. Immunodeficient mice have shown an increased frequency of tumor development compared to wild-type mice4,5. 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 carcinogenisis7,8. 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 genes12-15. 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 risk14. 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. PUBLIC HEALTH RELEVANCE: Since disease control and survival rates of patients with HNSCC have not improved significantly for most sites over the past 30 years there is a compelling need for new treatment approaches. Elucidating genetic determinants of immune-related host susceptibility to HNSCC through GWAS analysis can facilitate the identification of at-risk populations and aid in the development of novel immunotherapeutic strategies.

描述（由申请人提供）：头颈鳞状细胞癌 (HNSCC) 是全球第六大常见癌症，每年诊断出超过 500,000 例新病例1。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，但大多数接触者不会患上癌症，这表明遗传变异在易感性中发挥着一定作用。暴露者罹患癌症风险的一个潜在调节因素是宿主的免疫状态，这由免疫相关基因的变异性决定。基因工程小鼠为实体瘤模型中的癌症免疫监视提供了证据5。与野生型小鼠相比，免疫缺陷小鼠的肿瘤发生频率增加4,5。同样，免疫抑制患者患鳞状细胞癌的风险也会增加。 HPV 诱发的口咽癌 (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，但还不够充分7,8。因此，HNSCC 是分析调节实体瘤易感性的免疫基因的理想模型系统。 通常，调查 HNSCC 风险遗传决定因素的研究仅检查几个单核苷酸多态性 (SNP)，并重点关注致癌物代谢和 DNA 修复基因的变异12-15。这些研究的局限性包括检测中等风险序列变异的统计功效较低、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中等先验概率14。为了克服这些问题，我们将对国际头颈癌流行病学联盟进行的全基因组关联研究 (GWAS) 应用一种新的分析策略，使用假设驱动的多候选基因方法，并整合数据质量控制、候选基因排序和通路分析的改进方法。 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。该提案的目的是：1) 探索免疫相关基因的遗传变异与 HNSCC 易感性之间的关联，并确定与发生 HNSCC 风险增加相关的候选免疫相关基因。利用 GWAS 的数据，我们将评估候选基因变异与 HNSCC 风险之间的关联，并进行基于通路的 SNP 关联分析，以揭示与 HNSCC 风险的复杂免疫遗传学关联。我们还将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）对 HPV 诱导的 OPC 患者进行单独的 SNP 关联分析。 2) 通过使用基因组 DNA 的 PCR 分析进行复制研究，验证独立的 HNSCC 病例和对照队列中排名靠前的免疫相关基因。 公共卫生相关性：由于过去 30 年来大多数地区 HNSCC 患者的疾病控制和生存率并未显着改善，因此迫切需要新的治疗方法。通过 GWAS 分析阐明免疫相关宿主对 HNSCC 易感性的遗传决定因素，有助于识别高危人群，并有助于开发新型免疫治疗策略。