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

摘要 人乳头瘤病毒相关（HPV+）口咽鳞状细胞癌（OPSCC）的发病率 在美国，宫颈癌的发病率正在上升，现在甚至比宫颈癌还普遍。由于HPV疫苗接种率低 HPV感染和癌症诊断之间长达数十年的潜伏期，HPV+ OPSCC仍然是一种常见的癌症。 主要的健康问题，最可能的死亡原因是远处转移。而且因为 终生有害的治疗对幸存者的生活质量的影响，有必要确定一个子集， 能从降级治疗中获益的患者。我们的长期目标是区分HPV+患者 预后良好，最有可能从降级治疗中获益的患者，以及需要 或者更激进的方案我们的研究小组首先表征了HPV+ OPSCC的两种主要亚型， 鉴定HPV整合到宿主基因组中作为确定肿瘤亚型的驱动因素。 此外，我们和其他人已经表明HPV整合状态与总生存率相关。 在这项提案中，我们计划研究我们小组确定的HPV整合的三个下游效应， 其他：HPV癌基因E6至E6* 剪接增加，肿瘤免疫应答降低，以及 细胞分化状态的变化。这些效应中的每一种都在决定转移和 然而，它们的作用机制及其相对贡献仍不清楚。在目标1中， 使用一种新的研究方法，解开HPV整合对总体和疾病特异性生存的上述三种影响， 密歇根大学的300名患者队列，我们将比较定义HPV整合的方法 status.我们还将基于H&E载玻片优化肿瘤免疫浸润的生物标志物。在目标2中，我们将 检查表达较短E6* 同种型而不是全长E6的转变的致癌作用，使用 体外和体内模型。我们和其他人观察到这会增加氧化磷酸化， 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* 表达的转变调节细胞侵袭和治疗的机制 反应根据我们的结果，我们将开始一个或多个基于生物标志物的试点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.