Immuno-inflammatory Response Non-coding RNAs as Predictors of HPV Status & Outcome of Oropharyngeal Cancer Patients

项目摘要 口咽部鳞状细胞癌是一种高致病性、危及生命的疾病。尽管 随着吸烟率的下降，SCCOP的发病率正在上升，特别是在年轻人中。这 这一趋势是人口中致癌性人乳头瘤病毒（HPV）感染流行率上升的结果。 大多数（约70-80%）SCCOP患者为HPV阳性[HPV（+）]。HPV（+）SCCOP是不同的 HPV阴性[HPV（-）] SCCOP的流行病学、临床和分子特征，尤其是 在临床行为、治疗反应和生存率方面。因此，在SCCOP患者中， HPV状态的确定对于确定预后和定制治疗是至关重要的。不幸的是 目前尚无有效的筛查方法来鉴别肿瘤HPV（+）SCCOP患者。此外，在患者中 对于HPV（+）SCCOP，临床结局仍存在异质性。SCCOP患者的识别 需要强化治疗和那些能够从降低治疗强度中受益的人， 有效和较少的病态治疗。影响免疫炎症反应的非编码RNA（ncRNA） 控制HPV清除和逃避免疫监视，并可能有助于肿瘤HPV状态和相关 SCCOP患者的临床结局。NcRNA在人血清中表现出稳定表达。我们假设 免疫炎症反应ncRNA的治疗前血清表达谱与肿瘤相关 HPV（+）SCCOP和相关临床结局。该项目的具体目标如下：目标1： 确定所选免疫炎症反应ncRNA的治疗前血清表达谱是否 在招募、治疗和随访的1500例SCCOP患者队列中检测肿瘤HPV状态标志物 德克萨斯大学医学博士安德森癌症中心。目的2：确定治疗前血清表达 选择的免疫炎症反应ncRNA谱预测疾病特异性生存，无病 目标1所述队列中HPV（+）SCCOP患者的生存率和总生存率。目标3： 验证目标1和目标2中发现的重要关联。我们将使用625例SCCOP病例的独立队列 以控制潜在的假阳性或无偏估计的关联。目标4：描述 免疫炎症反应ncRNA对体外肿瘤放射敏感性的影响。我们将筛查一组HPV（+） SCCOP细胞系在临床环境中检测感兴趣的ncRNA，以进一步验证这些预后性ncRNA 在目标2中找到。这项功能研究将验证这些ncRNA中的一种或多种作为生物标志物， 纳入预后预测模型，以实现更个性化的治疗。鉴定新 肿瘤HPV状态和HPV（+）患者预后的生物标志物SCCOP将使医生能够更多地 有效地为有HPV（+）SCCOP风险患者量身定制筛查以及治疗和监测策略 优化HPV（+）SCCOP患者的生存率和生活质量。

PROJECT SUMMARY Squamous cell carcinoma of the oropharynx (SCCOP) is a highly morbid, life-threatening disease. Despite declining smoking prevalence, the incidence of SCCOP is increasing, particularly among younger adults. This trend is the result of the rising prevalence of oncogenic human papillomavirus (HPV) infection in the population. The majority (approximately 70-80%) of SCCOP patients are HPV-positive [HPV(+)]. HPV(+) SCCOP is distinct from HPV-negative [HPV(-)] SCCOP in terms of epidemiologic, clinical, and molecular features, and especially in terms of clinical behavior, response to treatment and survival. Therefore, in patients with SCCOP, determination of HPV status is critical for defining prognosis and tailoring therapy. Unfortunately, there is currently no effective screening method to identify patients with tumor HPV(+) SCCOP. Further, among patients with HPV(+) SCCOP, there remains heterogeneity in clinical outcomes. Identification of patients with SCCOP needing treatment intensification and those able to benefit from reduction of treatment intensity is critical to more effective and less morbid treatment. Noncoding RNAs (ncRNAs) that affect the immuno-inflammatory response control HPV clearance and escape of immune surveillance, and may contribute to tumor HPV status and related clinical outcomes of SCCOP patients. NcRNAs exhibit stable expression in human serum. We hypothesize that pretreatment serum expression profiles of immuno-inflammatory response ncRNAs are associated with tumor HPV(+) SCCOP and related clinical outcomes. The specific aims for this project are as follows: Aim 1: To determine if pretreatment serum expression profiles of selected immuno-inflammatory response ncRNAs are markers of tumor HPV status in a cohort of 1500 patients with incident SCCOP recruited, treated, and followed at The University of Texas MD Anderson Cancer Center. Aim 2: To determine if pretreatment serum expression profiles of selected immuno-inflammatory response ncRNAs predict disease-specific survival, disease-free survival, and overall survival among HPV(+) SCCOP patients from the cohort described for Aim 1. Aim 3: To validate significant associations found in Aims 1 and 2. We will use an independent cohort of 625 SCCOP cases to control for potential false-positive or unbiased estimates of associations. Aim 4: To characterize functions of immuno-inflammatory response ncRNAs on tumor radiosensitivity in vitro. We will screen a panel of HPV(+) SCCOP cell lines for ncRNAs of interest in a clinical setting, in order to further validate these prognostic ncRNAs found in Aim 2. This functional study will validate 1 or more of these ncRNAs as biomarkers that can be incorporated into prognostic prediction models to permit more personalized treatment. Identifying novel biomarkers for tumor HPV status and prognosis of patients with HPV(+) SCCOP will allow physicians to more effectively tailor screening for patients at risk of HPV(+) SCCOP, as well as treatment, and surveillance strategies that optimize survival and quality of life for patients with HPV(+) SCCOP.