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发病率最高，其中很大一部分人口是农村， 经济上处于不利地位，医疗服务不足。阿巴拉契亚人是世界上烟草使用量最高的地区。 在一个国家，这种行为与HNC的发病率和死亡率的差异直接相关。因此，迫切需要确定 导致烟草阳性的阿巴拉契亚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。中国人群单基因信息学分析 研究小组已经确定了与吸烟相关的多个基因的拷贝数增加。这些基因中的大多数映射到 染色体11 q13细胞带，HNC中最常扩增的区域，长期以来被认为与 减少生存。11 q13扩增子中过表达的13个吸烟相关基因对应于减少的吸烟相关基因。 生存率、死亡风险增加和淋巴结转移风险增加。虽然这个区域的一些基因已经被 作为HNC进展的驱动因素，这项分析鉴定的其他基因在癌症中的作用尚不清楚， 为治疗干预提供了新的靶点。本提案的总体目标是确定以下方面的作用： 来自11 q13扩增子中吸烟相关表达特征（SAES）的未表征基因， 肿瘤进展的阿巴拉契亚烟草阳性HNC-。我们的中心假设是， SAES中的11 q13基因有助于降低阿巴拉契亚HPV存活率。非特征性肿瘤的致癌性筛查 将进行SAES基因，以评估每个基因在促进癌症标志中的个体贡献。的sae 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来评估基因功能。 HNSCC模型。目的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11 q13扩增的HNC-。目标2将利用实验和临床平行成像 用于单独评估淋巴结转移的新预测驱动因素的模式。这些基因将被检测 促进11 q13扩增的阿巴拉契亚HNC中的肿瘤细胞生长、淋巴结扩散、代谢改变和增殖- 肿瘤的全面了解每个新的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11 q13扩增子如何导致总体不良结果的知识中的关键空白 可见于烟草相关的HNC-。该提案的结果将为未来的研究提供基础， 机械地解决从这项工作中鉴定的新的肿瘤促进SAES基因作为疾病侵袭性的驱动因素， 潜在地用作治疗开发的新靶标和/或生物标志物以改善这种高度恶性肿瘤的治疗。 阿巴拉契亚人的难治性疾病