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

项目摘要 任何女性都不应该死于宫颈癌。我们拥有技术、医疗和政策工具和方法 来消除它。然而，每两分钟就有一名妇女死于宫颈癌。宫颈癌排在第三位。 继乳腺癌和结直肠癌之后，世界上女性中的恶性肿瘤。宫颈癌也是 在世界范围内存在着最明显差异的肿瘤。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预先检查的机会不同。 癌症或预防性治疗；各国之间也存在类似的差异。最近出版的 美国子宫切除校正的宫颈癌死亡率显示出更大的种族差异 黑人女性，这是之前计算过的，并显示年龄最大的黑人女性的宫颈最高 癌症死亡率。尽管如此，超过80%的病例和88%的死亡发生在低血压病 和中等收入国家(LMIC)。世界卫生组织(WHO)制定了关于 宫颈上皮内瘤变2-3的治疗和预防宫颈癌的筛选和治疗策略。 在以细胞学为基础的宫颈癌筛查存在多个障碍的国家，各种替代方案 正在使用的算法包括低成本致癌HPV检测，用醋酸进行目视检查， 和自己收集的阴道拭子。HPV检测是宫颈癌细胞学检查的一种很好的替代方法 放映。然而，HPV检测确定了患宫颈癌的风险，但不能确定那些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。 目前的做法是对这些妇女进行进一步的细胞学和阴道镜活检检测 发达国家和LMICs的切除或消融治疗。使用DNA生物标记物可以减少 在保持足够的敏感度和特异度的同时参考阴道镜检查的妇女人数。在这一速度中 跟踪SBIR项目，我们建议论证了将一种精度商业化的可行性 甲基化检测，CervicalMethDx检测，作为一种反射，对HPV阳性的宫颈癌高危患者进行分层 测试LMIC中现有的护理标准。我们的测试将使HPV+女性能够识别出临床上有风险的 从低度鳞状上皮内病变到宫颈上皮内瘤变的进展 三年级(CIN3)。在将不实施基于宫颈细胞学的筛查的LMIC中，可选 我们的检测方法将在未来的项目中开发，以对HPV+高宫颈风险女性进行分层 自己采集的阴道拭子和/或尿样中的癌症。我们正在与大卫·西德兰斯基的 研究实验室优化CervicalMethDx测试和Estanpa研究(NCT01881659) 向洪都拉斯、哥伦比亚、阿根廷和澳大利亚的居民推出精确表观遗传服务的财团 巴拉圭。对HPV+妇女进行有效的分流将减少不必要的治疗，提高医疗质量， 降低医疗保健成本，减少低收入国家宫颈癌死亡率差距。

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.