Abstract：
The highest frequency of genetic alterations in the tumor suppressor ARID1A occurs in malignancies of the female reproductive tract. The prevalence of ARID1A alterations in gynecologic precancers and cancers is summarized from the literature, and the putative mechanisms of tumor suppressive action examined both in benign/precursor lesions including endometriosis and atypical hyperplasia and in malignancies of the ovary, uterus, cervix and vagina. ARID1A alterations in gynecologic cancers are usually loss-of-function mutations, resulting in diminished or absent protein expression. ARID1A deficiency results in pleiotropic downstream effects related not only to its role in transcriptional regulation as a SWI/SNF complex subunit, but also related to the functions of ARID1A in DNA replication and repair, immune modulation, cell cycle progression, endoplasmic reticulum (ER) stress and oxidative stress. The most promising actionable signaling pathway interactions and therapeutic vulnerabilities of ARID1A mutated cancers are presented with a critical review of the currently available experimental and clinical evidence. The role of ARID1A in response to chemotherapeutic agents, radiation therapy and immunotherapy is also addressed. In summary, the multi-faceted role of ARID1A mutation in precancer and cancer is examined through a clinical lens focused on development of novel preventive and therapeutic interventions for gynecological cancers.
摘要：
肿瘤抑制因子ARID1A的遗传改变频率最高发生在女性生殖道的恶性肿瘤中。从文献中总结了妇科癌前病变和癌症中ARID1A改变的患病率，并且在良性/前体病变包括子宫内膜异位症和非典型增生以及卵巢恶性肿瘤中检查了肿瘤抑制作用的假定机制，子宫,宫颈和阴道。妇科癌症中的ARID1A改变通常是功能丧失突变，导致蛋白质表达减少或缺失。ARID1A缺乏导致多效性下游效应，不仅与其作为SWI/SNF复合物亚基在转录调控中的作用有关，而且与ARID1A在DNA复制和修复中的功能有关，免疫调节，细胞周期进程，内质网（ER）应激和氧化应激。ARID1A突变癌症的最有前途的可操作信号通路相互作用和治疗脆弱性提出了对目前可用的实验和临床证据的严格审查。ARID1A在化疗药物反应中的作用，放射治疗和免疫疗法也得到解决。总之,ARID1A突变在癌前病变和癌症中的多方面作用是通过临床研究重点关注妇科癌症新型预防和治疗干预措施的开发。
