Evaluation of smoking-associated genes in disparate Appalachian head and neck cancer

不同阿巴拉契亚头颈癌吸烟相关基因的评估

• 批准号: 10741961
• 负责人: Scott A Weed
• 金额: $ 22.8万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10741961
• 关键词: 11q13; 18F-fluorothymidine; 3-Dimensional; Ablation; Address; Apoptotic; Appalachian Region; Automobile Driving; Behavior; Biological Assay; Candidate Disease Gene; Carcinogens; Cell Cycle; Cell Line; Cell Proliferation; Cell physiology; Cells; Cervical; Cervical lymph node group; Cessation of life; Chromosome Mapping; Chromosomes; Chronic; Clinical; Clinical Data; Cultured Cells; DNA Damage; Data; Databases; Disease; Disparate; Disparity; Drug Targeting; Evaluation; Exposure to; Flow Cytometry; Foundations; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Induction; Genomics; Geography; Goals; Growth; HPV-negative head and neck cancer; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Histologic; Human Papillomavirus; Image; Incidence; Individual; Informatics; Invaded; Knowledge; Light; Lighting; Link; Lymph Node Involvement; Malignant Neoplasms; Measures; Medical; Membrane Fluidity; Membrane Microdomains; Metabolic; Metabolism; Metastatic Neoplasm to Lymph Nodes; Microscopy; Modeling; Molecular; Mouth Neoplasms; Mus; Nature; Nodal; Oncogenic; Oncology; Outcome; Pathologic; Patient-Focused Outcomes; Patients; Phenotype; Population; Positron-Emission Tomography; Proliferating; Property; Proteins; Publishing; Refractory; Refractory Disease; Research; Resistance; Rest; Risk; Risk Factors; Role; Rural; Rural Appalachia; Signal Transduction; Smoke; Smoking; Smoking Status; Structure; Survival Rate; System; Testing; Therapeutic Intervention; Tobacco; Tobacco use; Tongue; Tumor Promotion; Vulnerable Populations; Work; cancer imaging; cancer type; cell growth; chemical spill; cohort; drug candidate; druggable target; economic disparity; experimental study; fluorodeoxyglucose; gene function; genetic signature; head and neck cancer patient; high risk; imaging modality; improved; insight; knock-down; malignant mouth neoplasm; medically underserved; mortality; mortality risk; mouse model; neoplastic cell; new therapeutic target; novel; novel therapeutic intervention; overexpression; patient population; promoter; research clinical testing; research study; screening; survival disparity; therapeutic biomarker; therapeutic development; tobacco user; treatment stratification; tumor; tumor growth; tumor progression; tumor xenograft; waterborne

PROJECT SUMMARY Late-stage, HPV-negative (HPV-) head and neck squamous cell carcinoma (HNSCC) (or HNC-) is the most lethal form of HNSCC. HNC- occurs at the highest incidence in the Appalachian region, where a large segment of this population is rural, economically disadvantaged and medically underserved. The Appalachian population is the highest user of tobacco in the nation, a behavior directly linked to disparities in HNC- incidence and mortality. As such, there is a pressing need to identify the underlying genomic mechanisms responsible for the disparate survival in tobacco-positive Appalachian HNC- patients as an essential step towards improving medical outcomes for these patients. Single gene informatic analysis of national cohorts has identified elevated copies of multiple genes associated with smoking. The majority of these genes map to chromosome 11q13 cytobands, the most commonly amplified region in HNC- and long known to be associated with reduced survival. 13 smoking-correlated genes overexpressed from the 11q13 amplicon correspond with decreased survival, increased risk of death and elevated risk of lymph node metastasis. While some genes in this region have been well studied as drivers of HNC- progression, other genes identified by this analysis have unknown roles in cancer and may present new targets for therapeutic intervention. The overall goal of this proposal is to identify the roles of uncharacterized genes from the smoking-associated expression signature (SAES) in the 11q13 amplicon that contribute to neoplastic progression of Appalachian tobacco-positive HNC-. Our central hypothesis is that overexpression of novel 11q13 genes in the SAES contribute in driving reduced Appalachian HPV-survival. Oncogenic screening of uncharacterized SAES genes will be conducted to evaluate the individual contributions of each gene in promoting cancer hallmarks. SAES gene function will be assessed using cultured cells from Appalachian tobacco-positive patients and mouse orthotopic HNSCC models. Aim 1 will test the role of SAES genes in driving tumor cell growth, proliferation, invasion, and metabolic reprogramming in tobacco-induced 11q13 amplified HNC-. Aim 2 will utilize experimental and clinically-parallel imaging modalities to individually evaluate novel predicted drivers of lymph node metastasis. These genes will be tested for promoting tumor cell growth, nodal spread, altered metabolism and proliferation in 11q13 amplified Appalachian HNC- tumors. A comprehensive understanding of how each novel SAES gene contributes to enhancing this aggressive HPV- subtype will fill a key gap in our knowledge regarding how the 11q13 amplicon contributes to the overall poor outcomes seen in tobacco-associated HNC-. Results from this proposal will provide a foundation for future studies that will mechanistically address novel tumor-promoting SAES genes identified from this work as drivers of disease aggressiveness, potentially serving as new targets for therapeutic development and/or biomarkers to improve treatment of this highly refractory disease in the Appalachian population.

项目摘要 晚期，HPV阴性（HPV-）头部和颈部鳞状细胞癌（HNSCC）（或HNC-）是最致命的形式 HNSCC。 HNC-发生在阿巴拉契亚地区的最高发病率，大部分人口是乡村， 经济不利和医疗服务不足。阿巴拉契亚人口是烟草的最高用户 国家，这是与HNC发病率和死亡率差异直接相关的行为。因此，有迫切需要识别 负责烟草阳性阿巴拉契亚HNC患者不同生存的基本基因组机制 作为改善这些患者医疗结果的重要一步。民族的单基因信息分析 队列已经确定了与吸烟相关的多个基因的升高。这些基因的大多数映射到 染色体11q13细胞体，这是HNC-最常见的扩增区域，而渴望与之相关 降低生存。 13吸烟相关的基因从11q13 Amplicon过表达与降低相对应 生存，死亡风险增加以及淋巴结转移的风险升高。虽然该地区的某些基因已经 作为HNC进展的驱动因素的研究很好，该分析鉴定出的其他基因在癌症中具有未知的作用，可能 为治疗干预提供了新的目标。该提案的总体目标是确定 来自吸烟相关的表达特征（SAE）的未表征的基因在11q13扩增子中有助于有助于 阿巴拉契亚烟草阳性HNC-的肿瘤进展。我们的中心假设是新颖的过表达 SAE中的11季度基因有助于驱动降低的阿巴拉契亚HPV苏属生存。对未表征的致癌筛查 将进行SAE基因，以评估每个基因在促进癌症标志方面的个体贡献。 saes 将使用来自阿巴拉契亚烟草阳性患者和小鼠原位的培养细胞评估基因功能 HNSCC模型。 AIM 1将测试SAE基因在驱动肿瘤细胞生长，增殖，侵袭和代谢中的作用 在烟草诱导的11q13扩增HNC-中重新编程。 AIM 2将利用实验和临床并行成像 单独评估新型预测淋巴结转移驱动因素的方式。这些基因将进行测试 促进肿瘤细胞的生长，淋巴结扩散，新陈代谢改变和增殖，在113年扩增了阿巴拉契亚HNC- 肿瘤。对每个新颖SAE基因如何有助于增强这种侵略性的HPV-的全面了解 亚型将填补我们关于11q13扩增子如何贡献整体不良结果的关键差距 在与烟草相关的HNC-中看到。该提案的结果将为以后的研究提供基础 从这项工作中确定为疾病侵略性的驱动力的新型促进肿瘤的SAE基因的机械师介绍了新型肿瘤的SAE基因 有可能作为治疗性开发和/或生物标志物的新目标，以改善对这一高度的治疗 阿巴拉契亚人口的难治性疾病。