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: 8724452
• 负责人: Chaya Levovitz
• 金额: $ 4.01万
• 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/8724452
• 关键词: Accounting; Alcohols; B-Lymphocytes; Behavioral; Biological Models; Candidate Disease Gene; Carcinogen Metabolism; Carcinogens; Complex; Cutaneous; 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; Genomic DNA; 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; public health relevance; 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.

描述（由申请人提供）：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1。虽然大多数HNSCC病例与暴露于烟草和酒精或感染人乳头瘤病毒（HPV）有关，但大多数暴露的人不会患上癌症，这表明遗传变异在易感性中起作用。暴露者癌症进展风险的一个潜在调节因素是由免疫相关基因变异决定的宿主免疫状态2。基因工程小鼠为实体瘤模型的癌症免疫监测提供了证据5。与野生型小鼠相比，免疫缺陷小鼠显示出更高的肿瘤发展频率4,5。同样，免疫抑制患者发生SCC的风险也增加。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感染是致癌性的必要条件，但并不足以致癌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，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性（snp），并关注致癌物质代谢和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能力较低，假阳性结果，正发表偏倚，以及每个SNP单独赋予风险大幅增加的中等先验概率14。为了克服这些问题，我们将采用一种新的分析策略，对由国际头颈癌流行病学协会进行的全基因组关联研究（GWAS）进行分析，使用假设驱动的多候选基因方法，并整合改进的数据质量控制、候选基因排序和途径分析方法。我们认为宿主免疫相关基因的遗传变异与HNSCC易感性的改变有关。本研究的目的是：1)探索免疫相关基因的遗传变异与HNSCC易感性之间的关系，并确定与HNSCC发生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风险之间的关系，并进行基于通路的SNP关联分析，以揭示复杂的免疫遗传学与HNSCC风险之间的关联。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)通过基因组DNA的PCR分析，在HNSCC病例和对照组的独立队列中进行复制研究，验证高排名免疫相关基因。