Downstream effects of HPV integration on survival/metastasis in oropharyngeal cancer

摘要 人乳头瘤病毒相关性口咽鳞状细胞癌的发病率 在美国正在上升，现在甚至比宫颈癌更普遍。由于HPV疫苗接种率较低 而HPV感染和癌症诊断之间长达数十年的潜伏期，HPV OPSCC仍然是一种 主要的健康问题，最有可能的死亡原因是远处转移。此外，由于 终生有害的治疗对幸存者的生活质量的影响，至关重要的是确定 将从降级治疗中受益的患者。我们的长期目标是区分HPV患者 他们预后良好，最有可能从降级治疗中受益，以及那些需要 标准的，或者更激进的养生法。我们的小组首先确定了HPV OPSCC的两个主要亚型， 确定HPV整合到宿主基因组中是确定肿瘤亚型的驱动因素。 此外，我们和其他人已经证明，HPV整合状态与总存活率有关。 在这项提案中，我们计划研究我们小组确定的HPV整合的三个下游影响和 其他：HPV癌基因E6到E6*剪接增加，肿瘤免疫反应下降，以及 细胞分化状态的改变。这些影响中的每一种都在确定转移和 然而，它们的作用机制和相对贡献仍不清楚。在目标1中，我们将 通过一项新的研究，理清HPV整合对总体和疾病特异性存活率的上述三个影响 密歇根大学300名患者的队列，我们将比较定义HPV整合的方法 状态。我们还将基于H&E玻片优化肿瘤免疫渗透的生物标记物。在目标2中，我们将 用以下方法研究E6*亚型转变为表达较短的E6*亚型而不是全长E6的致癌效应 体外和体内模型。我们和其他人观察到这是为了增加氧化磷酸化和 潜在的肿瘤突变负担。最后，在目标3中，我们将使用体外和体内模型来检查 HPV整合和/或向E6*表达转变调节细胞侵袭和治疗的机制 回应。根据我们的结果，我们将开始一项或多项基于生物标记物的中试II期临床试验。

Abstract The incidence of human papillomavirus associated (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) is rising in the US, and is now even more prevalent than cervical cancer. Due to low HPV vaccination rates and the decades long latency period between HPV infection and cancer diagnosis, HPV+ OPSCC remains a major health concern, with the most likely reason for death being distant metastasis. Furthermore, due to the life-long detrimental treatment effects on quality of life for survivors, it is essential to identify a subset of patients who would benefit from de-escalated treatment. Our long term goal is to differentiate HPV+ patients who have a good prognosis and are most likely to benefit from de-escalated therapy and those who require the standard, or a more aggressive regimen. Our group first characterized two main subtypes of HPV+ OPSCC, identifying HPV integration into the host genome as the driving factor in determining tumor subtype. Furthermore, we and others have shown that HPV integration status is associated with overall survival. In this proposal we plan to study three downstream effects of HPV integration identified by our group and others: an increase in the splicing of HPV oncogene E6 to E6*, a decrease in the tumor immune response, and a change in cell differentiation status. Each of these effects plays a role in determining metastasis and survival, however the mechanism of their effect and their relative contributions remain unclear. In aim 1, we will disentangle the above three effects of HPV integration on overall and disease-specific survival using a University of Michigan cohort of 300 patients, and we will compare methods for defining HPV integration status. We will also optimize a biomarker for tumor immune infiltration based on H&E slides. In aim 2, we will examine the oncogenic effects of the shift to expressing the shorter E6* isoform instead of full length E6, using in vitro and in vivo models. This was observed by us and others to increase oxidative phosphorylation and potentially tumor mutational burden. Finally, in aim 3 we will use in vitro and vivo models to examine mechanism by which HPV integration and/or the shift to E6* expression modulate cell invasion and treatment response. Based on our results, we will begin one or more biomarker-based pilot phase II clinical trials.