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: 10652422
• 负责人: Robert D Burk
• 金额: $ 57.16万
• 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/10652422
• 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 Cancer Screening; 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 Vaccination; 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; Vaccines; Viral; Viral Genome; Virus Integration; Woman; cancer cell; cancer invasiveness; carcinogenesis; cell dedifferentiation; clinical application; cohort; comparison control; cost; cost effective; gene panel; integration site; molecular marker; next generation sequencing; premalignant; 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，超过12,000名妇女被诊断出患有宫颈癌，是HPV相关的恶性肿瘤 美国有两种主要的组织学形式的子宫颈癌：鳞状细胞癌（SCC）和 腺癌（腺癌）。重要的是，可以通过宫颈细胞学筛查来预防SCC 程序，而阿迪诺不能。虽然有针对HPV的预防性疫苗，但吸收HPV 美国的疫苗接种很差，有几代妇女已经暴露 HPV感染，HPV疫苗接种将无法帮助。因此，宫颈筛查费用超过6美元 至少几十年来每年需要十亿美元。了解 Adeno具有重要的公共健康价值，以促进预防Adeno，目前 筛选策略不足。在美国和欧洲，HPV16、18和45个感染量> 95％ AIS/ADENO。我们检查了HPV16/18/45 AI（n = 27）和颈椎内的病毒甲基化 肿瘤3级（CIN3）（n = 63）病例，而90 HPV16/18/45对照感染<cin2，发现 HPV16的AUC分别为0.99和0.82。此外，我们还有初步数据表明 与对照组相比 （<cin2）。此外，我们已经采用了HPV-DNA捕获NGS测定法来预期评估病毒 整合并发现了在整个筛选中保持特定的HPV18病毒整合。我们 进一步发现，该集成站点的HPV融合读取的读取性逐渐增加，并且 在直接覆盖之前的急剧峰值，对入射CIN3病变的组织学鉴定。 检测到的NGS可能代表了一个扩展的恶性细胞克隆，并且显示出强大的潜力 用于临床应用。 我们建议研究HPV和Adeno前体的自然历史（即在 诊断Adeno和AIS）的目的是定义Adeno的分子前体，这可能是 可以立即治疗，从而防止艾eno。我们将利用大量的队列 HPV16、18和45个阳性妇女（n> 20,000），其中绝大多数Adeno发生，以衡量宿主 HPV病毒甲基化变化和HPV病毒整合以分子定义的自然历史 阿迪诺。我们将将这些发现与SCC的自然史进行比较和对比。最终， 我们将使用HPV基因型，HPV病毒和宿主为AIS/ADENO前体开发风险预测模型 基因表观遗传学和HPV病毒整合。