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

项目总结 口咽鳞状细胞癌(SCCOP)是一种高度病态、危及生命的疾病。尽管 随着吸烟流行率的下降，SCCOP的发病率正在上升，特别是在年轻人中。这 这一趋势是致癌性人乳头瘤病毒(HPV)感染在人群中的流行上升的结果。 大多数(约70-80%)的SCCOP患者是HPV阳性[HPV(+)]。HPV(+)SCCOP是不同的 从流行病学、临床和分子特征上看HPV阴性的SCCOP，尤其是 在临床行为、对治疗的反应和生存方面。因此，在SCCOP患者中， HPV状态的确定对于确定预后和量身定制治疗至关重要。不幸的是，有 目前还没有有效的筛查方法来识别肿瘤HPV(+)SCCOP患者。此外，在患者中 对于HPV(+)SCCOP，临床结果仍然存在异质性。慢性阻塞性肺病患者的识别 需要强化治疗和那些能够从降低治疗强度中受益的人是更多 有效且病态较少的治疗。影响免疫炎症反应的非编码RNA(NcRNA) 控制HPV的清除和逃避免疫监视，可能与肿瘤的HPV状态有关 慢性阻塞性肺病患者的临床结局。NcRNAs在人血清中稳定表达。我们假设 治疗前血清免疫炎症反应ncRNAs表达谱与肿瘤相关 HPV(+)SCCOP及相关临床结局。这项计划的具体目标如下：目标1： 确定选定的免疫炎症反应ncRNAs的预处理血清表达谱是否 1500名SCCOP患者队列中肿瘤HPV状态的标志物招募、治疗和随访 在德克萨斯大学MD安德森癌症中心。目的2：确定治疗前血清表达 选定的免疫炎症反应ncRNA的特征可预测疾病特异性存活、无病生存 目标1中描述的队列中HPV(+)SCCOP患者的存活率和总体存活率。目标3：至 验证在AIMS 1和AIMS 2中发现的显著关联。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见的关联性估计。目标4：描述的功能 免疫炎症反应ncRNAs对肿瘤放射敏感性的影响。我们将筛选一组HPV(+) SCCOP细胞系用于临床环境中感兴趣的ncRNA，以便进一步验证这些预后ncRNAs 这项功能研究将验证其中一个或多个ncRNA作为生物标记物可以 合并到预后预测模型中，以实现更个性化的治疗。辨别小说 HPV(+)SCCOP患者肿瘤HPV状态和预后的生物标志物将使医生能够更多地 有效地为HPV(+)SCCOP高危患者量身定做筛查以及治疗和监测策略 优化HPV(+)SCCOP患者的生存和生活质量。

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.