Sun Qian, Wang Liangliang, Zhang Cong, Hong Zhenya, Han Zhiqiang
Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology, Wuhan 430030, Hubei, China.
Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China.
Biomark Res. 2022 Nov 17;10(1):85. doi: 10.1186/s40364-022-00428-7.
Cervical cancer is the first identified human papillomavirus (HPV) associated cancer and the most promising malignancy to be eliminated. However, the ever-changing virus subtypes and acquired multiple drug resistance continue to induce failure of tumor prevention and treatment. The exploration of cervical cancer heterogeneity is the crucial way to achieve effective prevention and precise treatment. Tumor heterogeneity exists in various aspects including the immune clearance of viruses, tumorigenesis, neoplasm recurrence, metastasis and drug resistance. Tumor development and drug resistance are often driven by potential gene amplification and deletion, not only somatic genomic alterations, but also copy number amplifications, histone modification and DNA methylation. Genomic rearrangements may occur by selection effects from chemotherapy or radiotherapy which exhibits genetic intra-tumor heterogeneity in advanced cervical cancers. The combined application of cervical cancer therapeutic vaccine and immune checkpoint inhibitors has become an effective strategy to address the heterogeneity of treatment. In this review, we will integrate classic and recently updated epidemiological data on vaccination rates, screening rates, incidence and mortality of cervical cancer patients worldwide aiming to understand the current situation of disease prevention and control and identify the direction of urgent efforts. Additionally, we will focus on the tumor environment to summarize the conditions of immune clearance and gene integration after different HPV infections and to explore the genomic factors of tumor heterogeneity. Finally, we will make a thorough inquiry into completed and ongoing phase III clinical trials in cervical cancer and summarize molecular mechanisms of drug resistance among chemotherapy, radiotherapy, biotherapy, and immunotherapy.
宫颈癌是首个被确认的与人乳头瘤病毒（HPV）相关的癌症，也是最有希望被消除的恶性肿瘤。然而，不断变化的病毒亚型和获得性多重耐药性持续导致肿瘤防治失败。探索宫颈癌异质性是实现有效预防和精准治疗的关键途径。肿瘤异质性存在于病毒的免疫清除、肿瘤发生、肿瘤复发、转移和耐药性等各个方面。肿瘤的发展和耐药性往往由潜在的基因扩增和缺失驱动，不仅包括体细胞基因组改变，还包括拷贝数扩增、组蛋白修饰和DNA甲基化。基因组重排可能通过化疗或放疗的选择效应发生，这在晚期宫颈癌中表现出肿瘤内基因异质性。宫颈癌治疗性疫苗与免疫检查点抑制剂的联合应用已成为应对治疗异质性的有效策略。在本综述中，我们将整合全球范围内宫颈癌患者疫苗接种率、筛查率、发病率和死亡率的经典及最新流行病学数据，旨在了解疾病防控现状并确定迫切需要努力的方向。此外，我们将聚焦肿瘤环境，总结不同HPV感染后免疫清除和基因整合的情况，并探索肿瘤异质性的基因组因素。最后，我们将深入探究已完成和正在进行的宫颈癌III期临床试验，并总结化疗、放疗、生物治疗和免疫治疗中的耐药分子机制。
