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

摘要 人乳头状瘤病毒（HPV（+））相关的口咽鳞状细胞癌的发病率 （OPSCC）在美国正在上升，现在估计它比宫颈癌更流行。 在OPSCC中存在显著差异，特别是在复发和生存方面， 非裔美国人OPSCC患者与非西班牙裔白色（NHW）OPSCC患者相比。由于低 HPV疫苗使用率以及HPV感染和癌症诊断之间长达数十年的潜伏期， HPV（+）OPSCC仍然是一个主要的健康问题。HPV（+）OPSCC患者的5年生存率为80%， 显著低于浸润性乳腺癌估计的90%，最可能的死亡原因是 远处转移非裔美国人的有限数据表明，与NHW相比，生存率低1.6倍 OPSCC，在这个种族群体中很少有HPV特异性研究。此外，由于长期的不利影响， 治疗对生存者生活质量的影响，确定一个患者子集是非常有意义的， 从降级治疗中获益。我们对父母补助金的长期目标是区分HPV（+） 预后良好且最有可能从减量治疗中获益的患者，以及 需要标准的或者更激进的治疗方案我们的研究小组首先描述了两种主要的亚型， HPV（+）OPSCC，将HPV整合到宿主基因组中作为决定肿瘤的驱动因素 亚型我们还发现HPV整合状态与总生存率相关。 在这项提案中，我们将把我们的父母资助计划扩展到来自美国的非洲裔OPSCC患者队列。 路易斯安那州肿瘤登记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存活中起作用， 然而，其作用机制及其相对贡献仍不清楚。在目标1中， 使用150个HPV整合对总体和疾病特异性生存率的上述三种影响， 来自路易斯安那州肿瘤登记处的非裔美国人OSPCC肿瘤，我们将这些肿瘤与我们的 密歇根州的NHW肿瘤。在目标2中，我们将考察主要表达较短的 在这些肿瘤中，E6* 亚型而不是全长E6。我们和其他人观察到， 磷酸化和潜在的肿瘤突变负荷。这些研究是关键的第一步， 了解HPV（+）OPSCC在非洲裔美国人中的分子后果，以确定 改善这一未充分研究组的预后。

ABSTRACT The incidence of human papillomavirus associated (HPV(+)) oropharyngeal squamous cell carcinoma (OPSCC) is rising in the US, to the point that it is now estimated to be more prevalent than cervical cancer. There are significant disparities in OPSCC, especially with respect to recurrence and survival, which is worse in African-American OPSCC patients compared to non-Hispanic White (NHW) OPSCC patients. Due to low HPV vaccine use rates and the decades long latency period between HPV infection and cancer diagnosis, HPV(+) OPSCC remains a major health concern. The 5 year survival rate for HPV(+) OPSCC patients is 80%, significantly lower than the estimated 90% for invasive breast cancer, and the most likely reason for death is distant metastasis. Limited data in African-Americans indicate 1.6-times worse survival compared to NHW OPSCC, with few HPV-specific studies in this racial group. Furthermore, due to the life-long detrimental treatment effects on quality of life for survivors, it is of great interest to identify a subset of patients who would benefit from de-escalated treatment. Our long term goal for the parent grant is to differentiate between 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 the two main subtypes of HPV(+) OPSCC, identifying HPV integration into the host genome as the driving factor in determining tumor subtype. We furthermore showed that HPV integration status is associated with overall survival. In this proposal we will extend our parent grant plan to a cohort of African-American OPSCC patients from the Louisiana Tumor Registry 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 150 African-American OSPCC tumors from the Louisiana Tumor Registry, and we will compare these tumors to our NHW tumors from Michigan. In aim 2, we will examine the effects of the shift to expressing mainly the shorter E6* isoform instead of full length E6 in these tumors. This was observed by us and others to increase oxidative phosphorylation and potentially tumor mutational burden. These studies are a first critical step to understanding the molecular consequences of HPV(+) OPSCC in African-Americans to identify avenues to improve prognosis in this understudied group.