Enlisting HPV integration events to illuminate drivers and target treatment in invasive cervical cancer

项目总结 浸润性宫颈癌(ICC)每年在全球范围内导致近311,000名妇女死亡，估计有50% 到2040年死亡人数增加。在美国，国际刑事法院在平均寿命损失年数和 不成比例地影响少数群体和社会经济地位较低的妇女。女性与 晚期或复发的ICC很快就会对目前的化疗方案产生耐药性，约90% 两年内死亡。我们的目的是定义临床上相关和可靶向的ICC基因和途径 改善患者的治疗和结果。我们的中心假设是HPV整合事件--以及 它们对宿主基因组和表观基因组施加的变化--赋予疾病选择性优势 进展，并提供机会，以确定与治疗ICC相关的基因和途径。vbl.使用 癌症基因组图谱(TCGA)ICC队列(CESC)，我们开发了一条管道来识别整合 某些ICC中HPV整合以及基因组和/或表观基因组改变的检测基因(IDG) 其他ICC中的修改。我们管道的要素侧重于接近整合地点、克隆 整合事件的表示、患者和疾病特定的基因表达、与 ICC存活率和ICC改变的频率。对于这项提议，我们将扩大我们的发现渠道 对于新完成的多组学ICC队列，HTMCP(HIV+肿瘤分子特征 项目)，采用新技术并测试IDG对ICC的功能贡献以及 化学反应。这种对过多IDG的深入描述将有助于我们识别新的 目标/路径，这是朝着更好地治疗ICC的妇女迈出的关键一步。为此，我们将 追求以下具体目标：识别和筛选HTMCP中HPV整合站点的IDG 样品使用我们建立的流水线，长读DNA和cDNA测序，以及其他基因组 研究(目标1)，确定IDGs对ICC的功能贡献及其治疗靶点 在宫颈癌细胞系中使用siRNA介导的KD和/或CRISPR基因编辑的可能性 原位异种移植模型(AIM 2)，并确定其临床相关性和生物标志物潜力 IDGs(目标3)。

PROJECT SUMMARY Invasive cervical cancer (ICC) kills nearly 311,000 women each year worldwide with an estimated 50% increase in deaths by 2040. In the U.S., ICC ranks third for average years of life lost and disproportionately affects minority groups and women of low socioeconomic status. Women with advanced or recurrent ICC soon develop resistance to current chemotherapy options, and about 90% die within 2 years. Our intent is to define clinically relevant and targetable ICC genes and pathways to improve patients’ treatments and outcomes. Our central hypothesis is that HPV integration events—and the changes they exert on the host genome and epigenome—confer a selective advantage to disease progression and provide opportunities to pinpoint genes and pathways relevant to treating ICC. Using The Cancer Genome Atlas (TCGA) ICC cohort (CESC), we developed a pipeline to identify integration detected genes (IDGs) altered by HPV integration in some ICCs and by genomic and/or epigenomic modifications in other ICCs. Elements of our pipeline focus on proximity to the integration site, clonal representation of the integration event, patient- and disease-specific gene expression, association with ICC survival, and frequency of alteration in ICC. For this proposal, we will expand our discovery pipeline to a newly completed multi-omics ICC cohort, the HTMCP (HIV+ Tumor Molecular Characterization Project), incorporating new technology and testing the functional contribution of IDGs to ICC and chemoresponse. This in-depth characterization of a plethora of IDGs will help us identify novel targets/pathways which is a critical step towards better therapy for women with ICC. To this end, we will pursue the following Specific Aims: Identify and filter IDGs from HPV integration sites in HTMCP samples using our established pipeline, long-read DNA and cDNA sequencing, and other genomic studies (Aim 1), determine the functional contribution of IDGs to ICC and their therapeutic targeting potential using siRNA-mediated KD and/or CRISPR-based gene editing in cervical cancer cell lines and orthotopic xenograft models, (Aim 2), and determine the clinical relevance and biomarker potential of IDGs (Aim 3).