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

项目总结 晚期HPV阴性(HPV-)头颈部鳞状细胞癌(HNSCC)(或HNC-)是最致命的 HNSCC。HNC-在阿巴拉契亚地区发病率最高，那里的大部分人口是农村人， 经济上处于不利地位，医疗上得不到充分的服务。阿巴拉契亚地区的人口是世界上烟草使用量最高的地区。 这一行为与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患者不同存活率的潜在基因组机制 作为改善这些患者的医疗结果的重要一步。全国人群单基因信息学分析 队列已经发现了与吸烟相关的多个基因拷贝的增加。这些基因中的大多数都映射到 染色体11q13细胞带，是HNC中最常见的扩增区域，长期以来一直被认为与 降低了存活率。11q13扩增子过度表达的13个吸烟相关基因对应于 存活率增加，死亡风险增加，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，这项分析确定的其他基因在癌症中的作用尚不清楚，可能 提出治疗干预的新靶点。这项提案的总体目标是确定 11q13扩增子中吸烟相关表达特征(SAE)的未知基因有助于 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 11q13基因在驱动阿巴拉契亚人乳头瘤病毒存活率降低中起作用。未定性的致癌基因筛查 SAEs基因将被用于评估每个基因在促进癌症标志方面的单独贡献。SAE 基因功能将使用阿巴拉契亚烟草阳性患者的培养细胞和小鼠原位移植进行评估 HNSCC型号。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11q13中的重编程扩增了HNC-。目标2将利用实验和临床平行成像 单独评估新的预测的淋巴转移驱动因素的方法。这些基因将被检测出 11q13扩增的阿巴拉契亚HNC-促进肿瘤细胞生长、结节扩散、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的HPV- 亚型将填补我们关于11q13扩增如何导致总体不良结果的知识中的一个关键空白 可见于与烟草相关的HNC-。这项提案的结果将为未来的研究提供基础， 从机制上解决从这项工作中确定的作为疾病侵袭性驱动因素的新的促进肿瘤的SAEs基因， 有可能成为治疗开发和/或生物标记物的新靶点，以改善这种高度的治疗 阿巴拉契亚地区人口中的顽固性疾病。

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.