Determining the impact of ancestry on oropharyngeal cancer biology and treatment response.

摘要 口咽癌(OPC)是目前头颈部最常见的恶性肿瘤， 与人类乳头瘤病毒(HPV)相关的OPC已超过宫颈癌，成为最常见的HPV- 美国的相关恶性疾病。非洲裔美国人(AA)患者显示OPC肿瘤学较差 即使在对HPV效应进行调整后，结果也会对非AA患者产生影响。目前尚不清楚是否减少了 AA OPC患者的治疗反应和生存完全是由不公平的护理和其他因素驱动的 社会经济变量，或者它是否至少部分地受到祖先和 癌症生物学。以前没有研究使用足够的OPC临床数据集来解决这个问题 相关的基因组和转录组数据，以解决这个翻译上的重要问题。因此， 无法确定再生障碍性贫血患者的OPC治疗反应和存活率是否与 使用现有数据集的差异肿瘤生物学。 在这个应用中，我们将利用两个为再生障碍性贫血患者丰富的独特的OPC队列来检验假设 再生障碍性贫血患者的OPC发展伴随着更具侵袭性的肿瘤生物学，由一种 免疫抑制肿瘤免疫微环境(TIME)。在目标1中，我们将自我报告的种族和 计算OPC固有肿瘤生物学和治疗反应的祖先。具体地说，我们将测试 肿瘤细胞多核之间的相关性(侵袭性OPC生物学的一个特征最近被我们的 多机构OPC队列中的团队)，AA OPC患者的生存率和差异基因表达匹配 对非AA患者进行T分类、HPV状态和吸烟史。在目标2中，我们将自我关联 报告的种族和计算的祖先对先前未治疗的再生障碍性贫血的时间和治疗反应的变化 再生障碍性骨肉瘤复发/转移患者的免疫检查点抑制反应 疾病。对于这两组分析，我们将部署新的、经过验证的机器学习方法来分析 传统的组织学载玻片，旨在促进跨多个其他机构的快速临床翻译。 拟议研究的完成将首次建立种族/血统之间的联系 生物学行为和治疗反应。我们假设的成功验证将提供一个独特的 开发旨在扭转AAOPC管理的精确肿瘤学方法的机会 在这一研究不足的患者群体的癌症特定存活率中注意到的差异。

ABSTRACT Oropharyngeal cancer (OPC) is now the most common malignancy of the head and neck region, and OPC associated with the human papillomavirus (HPV) has overtaken cervical cancer as the most common HPV- associated malignancy in the United States. African American (AA) patients demonstrate inferior OPC oncologic outcomes to their non-AA counterparts even when adjusting for HPV effect. It is not known whether reduced treatment response and survival in AA OPC patients is driven solely by unequitable access to care and other socio-economic variables or whether it is impacted at least partially by the interaction between ancestry and cancer biology. No previous study has addressed this question using an adequate OPC clinical dataset with correlative genomic and transcriptomic data in order to address this translationally important question. Therefore, it is not possible to determine whether OPC treatment response and survival in AA patients is partially linked to differential tumor biology using existing datasets. In this application, we will utilize two unique OPC cohorts enriched for AA patients to test the hypothesis that OPC development in AA patients is accompanied by more aggressive tumor biology facilitated by an immunosuppressive tumor immune microenvironment (TIME). In Aim 1 we will correlate self-reported race and calculated ancestry to intrinsic OPC tumor biology and treatment response. Specifically, we will test the correlation between tumor cell multi-nucleation (a feature of aggressive OPC biology recently validated by our team in a multi-institutional OPC cohort), survival, and differential gene expression in AA OPC patients matched to their non-AA counterparts for T classification, HPV status, and smoking history. In Aim 2 we will correlate self- reported race and calculated ancestry to changes in TIME and treatment response in previously untreated AA OPC patients as well as immune checkpoint inhibitor response in AA OPC patients with recurrent/metastatic disease. For both sets of analyses, we will deploy novel, validated machine learning approaches to analysis of conventional histologic slides designed to facilitate rapid clinical translation across multiple other institutions. Completion of the proposed studies will, for the first time, establish the link between race/ancestry, OPC biological behavior, and treatment response. Successful validation of our hypothesis will provide a unique opportunity for the development of precision oncology approaches to AA OPC management aimed at reversing the disparities noted in cancer specific survival for this understudied patient population.