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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要晚期 HPV 阴性 (HPV-) 头颈鳞状细胞癌 (HNSCC)（或 HNC-）是最致命的形式 HNSCC。 HNC- 在阿巴拉契亚地区发病率最高，该地区大部分人口是农村人口，经济上处于弱势且医疗服务不足。阿巴拉契亚人口是世界上烟草使用者最多的地区这种行为与 HNC 发病率和死亡率的差异直接相关。因此，迫切需要确定烟草阳性阿巴拉契亚 HNC 患者不同生存率的潜在基因组机制作为改善这些患者医疗结果的重要一步。国家单基因信息分析研究人员已经发现与吸烟相关的多个基因的拷贝数升高。这些基因中的大多数映射到染色体 11q13 细胞带，HNC 中最常见的扩增区域，长期以来已知与生存率降低。 11q13 扩增子中过度表达的 13 个与吸烟相关的基因与吸烟相关基因的减少相对应生存率、死亡风险增加和淋巴结转移风险增加。虽然该区域的一些基因已被作为 HNC 进展的驱动因素，经过充分研究，该分析确定的其他基因在癌症中具有未知的作用，可能提出了治疗干预的新目标。该提案的总体目标是确定以下人员的角色： 11q13 扩增子中与吸烟相关的表达特征 (SAES) 中未表征的基因有助于阿巴拉契亚烟草阳性 HNC- 的肿瘤进展。我们的中心假设是小说的过度表达 SAES 中的 11q13 基因有助于降低阿巴拉契亚 HPV 存活率。未表征的致癌筛查将进行 SAES 基因评估每个基因在促进癌症标志方面的个体贡献。高级工程师学会将使用来自阿巴拉契亚烟草阳性患者的培养细胞和小鼠原位评估基因功能 HNSCC 模型。目标 1 将测试 SAES 基因在驱动肿瘤细胞生长、增殖、侵袭和代谢中的作用烟草诱导的 11q13 扩增 HNC- 中的重编程。目标 2 将利用实验和临床并行成像单独评估淋巴结转移的新预测驱动因素的方式。这些基因将被测试促进 11q13 扩增的阿巴拉契亚 HNC 中的肿瘤细胞生长、淋巴结扩散、代谢和增殖改变肿瘤。全面了解每个新的 SAES 基因如何有助于增强这种侵袭性 HPV- 亚型将填补我们关于 11q13 扩增子如何导致总体不良结果的知识空白见于与烟草相关的 HNC-。该提案的结果将为未来的研究奠定基础机械地解决从这项工作中确定的新的肿瘤促进SAES基因作为疾病侵袭性的驱动因素，可能作为治疗开发和/或生物标志物的新靶点，以改善这种高度的治疗阿巴拉契亚人群中的难治性疾病。