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

HPV 整合对口咽癌生存/转移的下游影响

• 批准号: 10260028
• 负责人: LAURA ROZEK
• 金额: $ 21.7万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10260028
• 关键词: Address; African American; Age; Alcohol consumption; Automobile Driving; Biological; Biological Markers; Biology; Cell Differentiation process; Cessation of life; Characteristics; Clinical Trials; DNA Repair Pathway; Data; Disease; Distant Metastasis; Epidemic; Epidemiologist; Epidemiology; Genome; Goals; Grant; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Health; Human Papillomavirus; Human papilloma virus infection; Immune response; Incidence; Infection; Length; Life; Link; Louisiana; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Michigan; Molecular; Mutation; Neoplasm Metastasis; Not Hispanic or Latino; Oncogenes; Oropharyngeal; Oropharyngeal Squamous Cell Carcinoma; Oxidative Phosphorylation; Parents; Participant; Pathologic; Pathologist; Pathway interactions; Patients; Pattern; Phase II Clinical Trials; Play; Population; Positioning Attribute; Precision therapeutics; Prognosis; Protein Isoforms; Protocols documentation; Quality of life; RNA Splicing; Race; Recurrence; Regimen; Resources; Risk; Role; Sampling; Selection for Treatments; Severities; Smoking; Survival Rate; Survivors; Time; Tissue Banks; Treatment Protocols; Treatment-related toxicity; Tumor Subtype; Tumor-Infiltrating Lymphocytes; Tumor-infiltrating immune cells; Universities; Vaccines; base; cancer diagnosis; caucasian American; cell type; cohort; differential expression; epithelial to mesenchymal transition; high risk; improved; interest; malignant breast neoplasm; malignant oropharynx neoplasm; parent grant; patient subsets; prognostic; racial difference; racial disparity; radiation response; sex; survival disparity; transcriptome sequencing; treatment effect; treatment group; tumor; tumor registry; virtual

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.

抽象的 人乳头瘤病毒相关（HPV（+））口咽鳞状细胞癌的发病率 (OPSCC) 在美国呈上升趋势，目前估计其发病率比宫颈癌还要高。 OPSCC 存在显着差异，特别是在复发和生存方面，情况更糟 非洲裔美国 OPSCC 患者与非西班牙裔白人 (NHW) OPSCC 患者相比。由于低 HPV 疫苗的使用率以及 HPV 感染和癌症诊断之间数十年的潜伏期， 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%， 显着低于估计的浸润性乳腺癌 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，其生存率低 1.6 倍 OPSCC，针对该种族群体的 HPV 特异性研究很少。此外，由于对终生不利 治疗对幸存者生活质量的影响，确定一部分患者将非常感兴趣 受益于降级治疗。我们的家长补助金长期目标是区分 HPV(+) 预后良好且最有可能从降级治疗中受益的患者以及 需要标准或更积极的治疗方案。我们的小组首先描述了两种主要亚型 HPV(+) OPSCC，将 HPV 整合到宿主基因组中作为确定肿瘤的驱动因素 亚型。我们进一步表明 HPV 整合状态与总生存期相关。 在这项提案中，我们将把我们的家长资助计划扩展到来自美国的一群非裔美国 OPSCC 患者。 路易斯安那州肿瘤登记处将研究我们小组确定的 HPV 整合的三种下游效应 其他：HPV癌基因E6至E6*剪接增加，肿瘤免疫反应降低，以及 细胞分化状态的变化。这些效应中的每一个都在决定转移和存活方面发挥着作用， 然而，它们的作用机制及其相对贡献仍不清楚。在目标 1 中，我们将 使用 150 来阐明 HPV 整合对总体生存率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洲裔美国人 OSPCC 肿瘤，我们将这些肿瘤与我们的肿瘤进行比较 来自密歇根州的 NHW 肿瘤。在目标 2 中，我们将研究转向主要表达较短的内容的效果 在这些肿瘤中，E6* 同工型而不是全长 E6。我们和其他人观察到这会增加氧化 磷酸化和潜在的肿瘤突变负担。这些研究是关键的第一步 了解非裔美国人中 HPV(+) OPSCC 的分子后果，以确定治疗的途径 改善该研究组的预后。