The role of the microbiome in HPV-associated cervical cancer in women with HIV

微生物组在 HIV 感染女性 HPV 相关宫颈癌中的作用

基本信息

批准号：
10390413
负责人：
Anne-Catrin Uhlemann
金额：
$ 45.7万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-06 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10390413
关键词：
Adjuvant Therapy Affect Africa South of the Sahara Aftercare Algorithms Biological Markers Biopsy Cervical Cervical Cancer Screening Cervical Intraepithelial Neoplasia Cervix Uteri Cervix carcinoma Cessation of life Clinical Data Clinical Research Collaborations Colposcopy Communities Complex Country DNA sequencing Detection Development Diagnostic Disadvantaged Disease Effectiveness Enrollment Environment Etiology Excision Failure Female Future Generations Genes Genetic Growth HIV HPV-High Risk Health Human Papilloma Virus Vaccine Human Papillomavirus Human papilloma virus infection Human papillomavirus 16 Immunosuppression Incidence Infrastructure Integration Host Factors Lactobacillus Lead Lesion Malignant Neoplasms Malignant neoplasm of cervix uteri Metagenomics Methods Methyltransferase Molecular Monitor Morbidity - disease rate Mutagens Nested Case-Control Study Outcome Participant Pathogenesis Patients Phase Pilot Projects Play Predictive Value Primary Prevention Rapid diagnostics Recurrence Recurrent disease Research Support Resources Ribosomal RNA Risk Role Safety Sampling Screening for cancer South Africa South African Subgroup Swab Test Result Testing Therapeutic Time Toxin Treatment Failure Triage Universities Vagina Variant Viral Virus Woman Work base cervical cancer prevention cervicovaginal cervicovaginal microbiome commensal bacteria design diagnostic screening follow-up fungus genetic variant high risk host microbiota host-microbe interactions improved insight low and middle-income countries metagenome microbial microbial community microbiome microbiome alteration microbiota mortality new therapeutic target overtreatment phase 1 study phase 2 study point of care premalignant prevent prophylactic reproductive tract screening screening program tertiary prevention treatment response tumor progression unnecessary treatment vaginal microbiome

项目摘要

Cervical cancer remains an important cause of morbidity and mortality in women, in particular in HIV-infected women in low and middle-income countries (LMIC), such as South Africa. Testing for human papilloma virus (HPV), the etiological agent of cervical cancer has significantly improved screen-and-treat approaches at the point of care in LMIC. However, although persistence of high-risk HPV types is the primary cause of precancerous cervical intraepithelial neoplasia grade 2 and 3 (CIN2+) and invasive cervical carcinoma (ICC), its detection has a low positive predictive value, as only a small proportion of HPV+ women will progress to CIN or ICC. Therefore, there is a compelling need for “triaging” HPV-positive women, to reduce unnecessary treatment. Once precursor lesions are identified, they are treated by either ablative or excisional methods, depending on grade. Both of these methods have significant recurrence risk. Better predictors of high-risk recurrences at the time of treatment as well as potential markers for recurrence post-treatment are needed to drive down the incidence of cervical cancer. The key factors that promote cancer progression likely reside in the cervical environment, notably its local microbiome. Preliminary evidence suggests that increased bacterial diversity and the presence of Lactobacillus iners are associated with CIN2+. L. iners harbors a highly variable mobile genetic repertoire, containing methylases and toxins that may play a role in progression of cervical lesions. Elucidating which taxa or genes are predictive of disease state could enable the development of adjunct rapid diagnostics in HPV+ women. Here we propose to comprehensively study virus-microbiota-host interactions, specifically the interaction between HPV and lower genital tract commensal bacteria and fungi relevant to cervical cancer screening in HIV+ and HIV- women. Our group at Columbia University has a long- standing and highly-productive collaboration with the University of Cape Town, South Africa, with whom we have undertaken large clinical studies of cervical cancer prevention. We will leverage samples and clinical data already collected from two of these recent studies. In Aim 1, we will define whether the cervicovaginal bacterial and fungal communities distinguish between HPV-infected women who have or do not have CIN2+, stratified by HIV status. In Aim 2, we will test whether cervical microbial taxa at baseline, or changes in taxa over time, predict recurrence after ablative therapy at 6 or 12 months in women with HPV+/CIN2+. This will inform which patients require more monitoring, and guide the identification of potential “adjuvant” therapies to improve efficacy of screening programs by reducing recurrent disease after treatment. In Aim 3 we will apply metagenomics to identify microbial gene markers and structural genetic variants that predict cervical cancer treatment failure. Combined, our work will inform potential triage tests to reduce the number of women without cervical disease beginning treatment, increase the sensitivity for detecting women who are at high risk of treatment failure, and yield mechanistic insights to help guide the future development of adjunct therapeutics.

宫颈癌仍然是女性发病和死亡的一个重要原因，尤其是艾滋病毒感染者低收入和中等收入国家 (LMIC) 的女性，例如南非，进行人乳头瘤病毒检测。（HPV），子宫颈癌的病因已显着改善了筛查和治疗方法然而，尽管高危 HPV 类型的持续存在是导致中低收入国家 (LMIC) 的主要原因。 2 级和 3 级癌前上皮内瘤变 (CIN2+) 和浸润性宫颈癌 (ICC)，其检测的阳性预测值较低，因为只有一小部分 HPV+ 女性会进展为因此，迫切需要对 HPV 阳性女性进行“分类”，以减少不必要的情况。一旦发现前体病变，就可以通过消融或切除方法进行治疗，这两种方法都可以更好地预测高风险。需要治疗时的复发情况以及治疗后复发的潜在标志物降低宫颈癌发病率的关键因素可能在于促进癌症进展。宫颈环境，特别是其局部微生物组，初步证据表明细菌增加。惰性乳杆菌的多样性和存在与 CIN2+ 相关。惰性乳杆菌具有高度可变性。移动遗传库，含有可能在宫颈癌进展中发挥作用的甲基化酶和毒素阐明哪些分类群或基因可以预测疾病状态可以促进疾病的发展。我们建议对 HPV+ 女性进行辅助综合快速诊断。相互作用，特别是 HPV 与下生殖道共生细菌和真菌之间的相互作用我们哥伦比亚大学的研究小组在与艾滋病毒阳性和艾滋病毒阴性女性的宫颈癌筛查相关方面拥有长期的研究成果。我们与南非开普敦大学建立了长期且富有成效的合作关系已经开展了宫颈癌预防的大型临床研究，我们将利用样本和临床数据。在目标 1 中，我们将确定宫颈阴道细菌是否存在。和真菌群落区分有或没有 CIN2+ 的 HPV 感染女性，分层在目标 2 中，我们将测试基线时的宫颈微生物分类群或分类群随时间的变化。预测 HPV+/CIN2+ 女性消融治疗后 6 或 12 个月的复发情况。患者需要更多的监测，并指导识别潜在的“辅助”疗法以改善在目标 3 中，我们将应用通过减少治疗后疾病复发的筛查计划的功效。宏基因组学可识别预测宫颈癌的微生物基因标记和结构遗传变异结合起来，我们的工作将为潜在的分类测试提供信息，以减少没有治疗失败的女性数量。宫颈疾病开始治疗，提高检测高风险女性的敏感性治疗失败，并产生机制见解，以帮助指导辅助治疗的未来发展。