Investigations Into The Molecular Pathogenesis Of Cervical Glandular Neoplasias

宫颈腺瘤的分子发病机制研究

• 批准号: 9897227
• 负责人: Robert D Burk
• 金额: $ 55.95万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-02 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9897227
• 关键词: Adenocarcinoma; Adenocarcinoma In Situ; Age; Area Under Curve; Automobile Driving; Biological Assay; Biology; Biopsy; California; Cancer Etiology; Cells; Cervical; Cervical Adenocarcinoma; Cervical Intraepithelial Neoplasia; Clinical; Clone Cells; Colposcopy; Cytology; DNA; Data; Detection; Developed Countries; Development; Diagnosis; Epigenetic Process; Europe; Evaluation; Evolution; Exposure to; Frequencies; Generations; Genes; Genome; Genotype; Goals; Histologic; Human Papilloma Virus-Related Malignant Neoplasm; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; Human papillomavirus 18; In Situ Lesion; Infection; Infection Control; Investigation; Lesion; Malignant Neoplasms; Malignant Squamous Cell Neoplasm; Malignant neoplasm of cervix uteri; Measures; Methylation; Modeling; Molecular; Natural History; Natural Selections; Neoplasms; Oncogenes; Oncogenic; Pathogenesis; Prevention; Preventive vaccine; Process; Public Health; Reporting; Risk; Sample Size; Sampling; Specimen; Squamous cell carcinoma; Technology; Testing; Vaccination; Vaccines; Viral; Viral Genome; Virus Integration; Woman; cancer cell; cancer invasiveness; carcinogenesis; clinical application; cohort; cost; cost effective; gene panel; integration site; molecular marker; next generation sequencing; prevent; prophylactic; prospective; risk prediction model; screening; screening program; uptake; virtual

ABSTRACT More than 12,000 women are diagnosed with cervical cancer, an HPV-associated malignancy, annually in the U.S. There are two major histologic forms of cervix cancer: squamous cell carcinoma (SCC) and adenocarcinoma (ADENO). Importantly, SCC can be prevented through cervical cytology screening programs, whereas ADENO cannot. While there is a prophylactic vaccine against HPV, uptake of HPV vaccination in the U.S. has been poor and there are several generations of women who are already exposed to HPV infection and will not be helped by HPV vaccination. Therefore, cervical screening at a cost of over $6 billion per year will be needed for several decades at least. Understanding the molecular pathogenesis of ADENO has important public health value in order to facilitate the prevention of ADENO, for which current screening strategies are inadequate. In the US and Europe, HPV16, 18, and 45 infections account for >95% of AIS/ADENO. We examined viral methylation of HPV16/18/45 AIS (n=27) and cervical intraepithelial neoplasia grade 3 (CIN3) (n=63) cases compared to 90 HPV16/18/45 control infections with <CIN2, and found AUC's of 0.99 and 0.82 for HPV16, respectively. In addition, we have preliminary data showing that methylation levels of a host gene panel is significantly higher in AIS lesions (p<0.001) compared to controls (<CIN2). Furthermore, we have employed an HPV-DNA capture NGS assay to prospectively evaluate viral integration and found a specific HPV18 viral integration that is maintained for the entirety of the screening. We further found that this integration site has a progressive increase in HPV-integration reads leading up to, and with a dramatic spike in coverage directly preceding, the histological identification of an incident CIN3 lesion. The NGS detected integration likely represents an expanding malignant cell clone and shows strong potential for clinical application. We propose to investigate the natural history of HPV and ADENO precursors (i.e., samples prior to the diagnosis of ADENO and from AIS) with the goal of defining molecular precursors of ADENO, which could be amenable to immediate treatment and thus prevent ADENO. We will leverage cohorts with large numbers of HPV16, 18, and 45-positive women (n > 20,000) in whom the vast majority of ADENO occur, to measure host and HPV viral methylation changes and HPV viral integration to molecularly define the natural history of ADENO. We will compare and contrast these findings with the better known natural history of SCC. Ultimately, we will develop a risk-prediction model for AIS/ADENO precursors using HPV genotypes, HPV viral and host gene epigenetics, and HPV viral integration.

抽象的 每年有超过 12,000 名女性被诊断患有宫颈癌，这是一种与 HPV 相关的恶性肿瘤。 在美国，子宫颈癌有两种主要的组织学形式：鳞状细胞癌 (SCC) 和 腺癌（ADENO）。重要的是，可以通过宫颈细胞学筛查来预防鳞状细胞癌 程序，而 ADENO 则不能。虽然有针对 HPV 的预防性疫苗，但 HPV 的摄入量 美国的疫苗接种情况一直很差，几代女性已经暴露在病毒之中 HPV 感染，并且 HPV 疫苗接种无济于事。因此，宫颈癌筛查的费用超过6美元 每年至少需要数十亿美元。了解疾病的分子发病机制 ADENO 具有重要的公共卫生价值，有助于预防 ADENO，目前 筛查策略不充分。在美国和欧洲，HPV16、18和45感染占>95% AIS/ADENO 的。我们检查了 HPV16/18/45 AIS (n=27) 和宫颈上皮内的病毒甲基化 3 级肿瘤 (CIN3) (n=63) 病例与 90 例 <CIN2 的 HPV16/18/45 对照感染相比，发现 HPV16 的 AUC 分别为 0.99 和 0.82。此外，我们有初步数据表明 与对照组相比，AIS 病变中宿主基因组的甲基化水平显着升高 (p<0.001) (<CIN2)。此外，我们还采用了 HPV-DNA 捕获 NGS 检测来前瞻性评估病毒 整合并发现了特定的 HPV18 病毒整合，该整合在整个筛查过程中得以维持。我们 进一步发现，该整合位点的 HPV 整合读数逐渐增加，并且 在事件 CIN3 病变的组织学鉴定之前，覆盖率急剧上升。 NGS 检测到的整合可能代表了一个正在扩大的恶性细胞克隆，并显示出强大的潜力 供临床应用。 我们建议研究 HPV 和 ADENO 前体的自然史（即，在 ADENO 和 AIS 的诊断），目标是定义 ADENO 的分子前体，这可以是 适合立即治疗，从而预防 ADENO。我们将利用拥有大量人员的群体 绝大多数 ADENO 发生在 HPV16、18 和 45 阳性女性 (n > 20,000) 中，以测量宿主 HPV 病毒甲基化变化和 HPV 病毒整合，从分子角度定义自然史 阿德诺。我们将把这些发现与更为人所知的鳞状细胞癌自然史进行比较和对比。最终， 我们将使用 HPV 基因型、HPV 病毒和宿主开发 AIS/ADENO 前体的风险预测模型 基因表观遗传学和 HPV 病毒整合。