大部分的人类高临床分级浆液性上皮性卵巢癌（SEOC）常存在p53基因的突变以及RB、FOXM1途径的异常，部分SEOC患者存在生殖细胞或体细胞中的BRCA1/2基因突变和该基因的表观遗传修饰异常，但是这些基因变化与SEOC的确切关系一直是个谜。5月23日Cancer Research 杂志在线发表了Ludmila Szabova等的研究论文阐明了其中的奥秘。
应用腺病毒诱导的Cre条件性基因失活的小鼠模型，研究者分析了Rb、 p53 、Brca1 及 Brca2信号通路扰动在上皮性卵巢癌发生和进展中发挥的作用。抑癌基因RB失活促使表面上皮异常增生进展为临床I级肿瘤。在伴有或不伴有Brca1/2基因失活的情况下，p53双等位基因失活或其无义突变将导致临床IV级肿瘤。与人类SEOC患者类似，在小鼠中表现为腹膜内癌扩散、腹水以及远处转移。无偏性基因分析和代谢组学分析证实Rb、p53、Brca1/2三联突变的肿瘤与人类SEOC相对应，而不与其他腹膜内肿瘤对应。
总之，该研究为分析SEOC的病因学、治疗评价和生物标记提供了新的线索，还有助于提高上皮性卵巢癌的成像技术。（生物谷bioon.com)
doi:10.1158/0008-5472.CAN-11-3834
Perturbation of Rb, p53 and Brca1 or Brca2 cooperate in inducing metastatic serous epithelial ovarian cancer
Ludmila Szabova, Chaoying Yin, Sujata Bupp et al.
The majority of human high grade serous epithelial ovarian cancer (SEOC) is characterized by frequent mutations in p53 and alterations in the RB and FOXM1 pathways. A subset of human SEOC harbors a combination of germline and somatic mutations as well as epigenetic dysfunction for BRCA1/2. Using Cre-conditional alleles and intrabursal induction by Cre-expressing adenovirus in genetically engineered mice, we analyzed the roles of pathway perturbations in epithelial ovarian cancer initiation and progression. Inactivation of RB-mediated tumor suppression induced surface epithelial proliferation with progression to stage I carcinoma. Additional biall elic inactivation and/or missense p53 mutation in the presence or absence of Brca1/2 caused progression to stage IV disease. As in human SEOC, mice developed peritoneal carcinomatosis, ascites, and distant metastases. Unbiased gene expression and metabolomic profiling confirmed that Rb, p53, and Brca1/2-triple mutant tumors aligned with human SEOC,and not with other intraperitoneal cancers. Together, our findings provide a novel resource for evaluating disease etiology and biomarkers, therapeutic evaluation, and improved imaging strategies in epithelial ovarian cancer.
