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：
10159868
负责人：
Anne-Catrin Uhlemann
金额：
$ 45.97万
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/10159868
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 Genetic Structures 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 Structure 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.

宫颈癌仍然是女性病态和死亡率的重要原因，特别是在HIV感染的女性中低收入国家（LMIC）的妇女，例如南非。（HPV），宫颈癌的病因学剂显着改善了在但是，LMIC的护理。癌前颈椎肿瘤2和3（CIN2+）和浸润性宫颈癌（ICC），它的检测具有较低的阳性预测价值，因为只有少量的HPV+女性才能发展为因此，CIN或ICC。治疗曾经是先前的病变取决于成绩。治疗时的复发以及在处理后复发的潜在标记物被Neeed到降低宫颈癌的发生率。宫颈环境，特别是局部微生物组。多样性和与Cin2+相关的乳杆菌的存在。移动遗传食谱，可能在宫颈进展中发挥作用的甲基质和毒素。病变。 HPV+女性的辅助诊断。相互作用，特别是HPV与下生殖道评论与真菌之间的相互作用与HIV+和HIV Women中的宫颈癌筛查有关。我们与南非开普敦大学的站立和高度生产的合作，我们已经对宫颈癌进行大量临床研究。已经从AIM 1中的两项研究中收集。真菌群落区分HO HOVE或没有CIN2+的HPV感染的女性通过AIM 2，我们将测试基线时宫颈微生物分类单元在HPV+/CIN2+的女性中预测6或12个月的消融治疗后的复发。患者需要更多的监测，并指导对潜在“辅助”疗法的识别以改进筛查程序的功效通过减少治疗后的复发性疾病。识别微生物基因标记和结构性遗传变异的宏基因组学预测宫颈癌治疗失败，我们的工作将为潜在的分类测试提供信息宫颈疾病开始治疗，提高发现高风险的妇女的敏感性治疗失败并产生机理见解，以帮助指导未来的相邻治疗剂的发展。