Precision methylation biomarkers for cervical cancer prevention in low resource settings in Latin America

项目摘要 没有女性应该死于宫颈癌。我们拥有技术、医疗和政策工具和方法， 然而，每两分钟就有一名妇女死于宫颈癌。宫颈癌是第三大 在世界妇女中，恶性肿瘤仅次于乳腺癌和结肠直肠癌。子宫颈癌也是一种 在世界范围内存在最明显差异的肿瘤。发病率的巨大差异 高收入国家和低收入国家之间的差距主要是由于获得有效筛查和产前检查的机会不同， 癌症或预防性治疗;国家内部也存在类似的差异。最近发表 在美国，子宫颈切除术矫正的宫颈癌死亡率显示出更大的种族差异， 黑人妇女，以前计算，并显示，最古老的黑人妇女有最高的颈椎 癌症死亡率。尽管如此，超过80%的病例和88%的死亡发生在低 中等收入国家（LMIC）。世界卫生组织（世卫组织）制定了以下指南： 宫颈上皮内瘤变的治疗2-3和预防宫颈癌的筛查和治疗策略。 在基于细胞学的宫颈癌筛查存在多重障碍的国家， 正在使用的算法，包括低成本致癌HPV检测，用乙酸进行目视检查， 和自己采集的阴道拭子HPV检测是宫颈癌细胞学检查的一个很好的替代方法 筛选然而，HPV检测可以识别出有宫颈癌风险的女性，而不是HPV阳性的女性。 最有可能患有或在不久的将来发展为需要治疗的重大疾病的妇女。 目前的做法是通过进一步的细胞学和阴道镜活检来对这些妇女进行分类， 发达国家和中低收入国家的切除或消融治疗。DNA生物标记物的使用可以减少 在保持足够的敏感性和特异性的同时，接受阴道镜检查的妇女人数。在这个快 跟踪SBIR项目，我们建议证明商业化的可行性， 甲基化测试，CervicalMethDx测试，用于对HPV+患者进行宫颈癌高风险分层，作为反射 在中低收入国家进行现有护理标准的测试。我们的测试将能够识别HPV+女性的临床风险， 从低度鳞状上皮内病变（LSIL）进展为宫颈上皮内瘤变 3级（CIN 3）。在LMIC中，将不实施基于宫颈细胞学的筛查，可选 我们的测试模式将在未来的项目中开发，以分层HPV+宫颈癌高危妇女， 在自我收集的阴道拭子和/或尿液样本中发现癌症。我们和大卫·西德兰斯基的 研究实验室优化CervicalMethDx检测和ESTAMPA研究（NCT 01881659） 联合会向洪都拉斯、哥伦比亚、阿根廷和墨西哥的居民介绍精确的表观遗传服务。 巴拉圭. HPV阳性妇女的有效分诊将减少不必要的治疗，提高医疗保健质量， 降低卫生保健费用，减少中低收入国家宫颈癌死亡率的差异。

Project Summary No woman should die from cervical cancer. We have the technical, medical and policy tools and approaches to eliminate it. Yet, one woman dies of cervical cancer every two minutes. Cervical cancer is the third leading malignancy among women in the world, after breast and colorectal cancer. Cervical cancer is also one of the tumors in which the most glaring disparities exist worldwide. The dramatic disparity in incidence rates between high- and low-income countries is due primarily to differential access to effective screening and pre- cancer, or preventive, treatment; similar disparities also exist within countries. Recently published hysterectomy-corrected cervical cancer mortality rates in the United States reveal a larger racial disparity in black women, that previously calculated and shows that the oldest black women have the highest cervical cancer mortality rates. Nonetheless, more than 80 percent of cases and 88 percent of deaths occur in Low and Middle Income Countries (LMICs). The World Health Organization (WHO) has developed guidelines for treatment of cervical intraepithelial neoplasia 2-3 and screen-and-treat strategies to prevent cervical cancer. In countries where multiple barriers exist for cytology based cervical cancer screening, a variety of alternative algorithms are being used, which include low-cost oncogenic HPV testing, visual inspection with acetic acid, and self-collected vaginal swabs. HPV testing is an excellent alternative to cytology for cervical cancer screening. However, HPV tests identifies women at risk for cervical cancer, but not those HPV-positive women who are most likely to have, or to develop in the near future, significant disease requiring treatment. Current practice is to triage these women by further testing with cytology and colposcopy-driven biopsies in developed countries and excision or ablation therapy in LMICs. The use of DNA biomarkers can reduce the number of women referred to colposcopy while maintaining adequate sensitivity and specificity. In this Fast Track SBIR project, we propose to demonstrate the feasibility for the commercialization of a precision methylation test, the CervicalMethDx Test, to stratify HPV+ patients for high risk of cervical cancer, as a reflex test to existing standard of care in LMICs. Our test will enable identification of HPV+ women at clinical risk for advancement from low-grade squamous intraepithelial lesions (LSIL) to Cervical Intraepithelial Neoplasia grade 3 (CIN3). In LMICs, where cervical cytology based-screening will not be implemented, optional modalities of our test will be developed in future projects to stratify HPV+ women at high risk of cervical cancer in self-collected vaginal swabs and/or urine samples. We are partnering with David Sidransky's research laboratory to optimize the CervicalMethDx Test and with the ESTAMPA Study (NCT01881659) Consortium to introduce precision epigenetic services to residents of Honduras, Colombia, Argentina and Paraguay. Efficient triage of HPV+ women will decrease unnecessary treatment, improve health care quality, decrease health care costs, and reduce cervical cancer mortality disparities in LMICs.