大部分的人類高臨床分級漿液性上皮性卵巢癌（SEOC）常存在p53基因的突變以及RB,、FOXM1途徑的異常，部分SEOC患者存在生殖細胞或體細胞中的BRCA1/2基因突變和該基因的表觀遺傳修飾異常,，但是這些基因變化與SEOC的確切關系一直是個謎。5月23日Cancer Research 雜志在線發(fā)表了Ludmila Szabova等的研究論文闡明了其中的奧秘,。
應用腺病毒誘導的Cre條件性基因失活的小鼠模型,，研究者分析了Rb、 p53 ,、Brca1 及 Brca2信號通路擾動在上皮性卵巢癌發(fā)生和進展中發(fā)揮的作用,。抑癌基因RB失活促使表面上皮異常增生進展為臨床I級腫瘤。在伴有或不伴有Brca1/2基因失活的情況下,，p53雙等位基因失活或其無義突變將導致臨床IV級腫瘤,。與人類SEOC患者類似，在小鼠中表現(xiàn)為腹膜內癌擴散,、腹水以及遠處轉移,。無偏性基因分析和代謝組學分析證實Rb、p53,、Brca1/2三聯(lián)突變的腫瘤與人類SEOC相對應,，而不與其他腹膜內腫瘤對應。
總之,，該研究為分析SEOC的病因學,、治療評價和生物標記提供了新的線索,，還有助于提高上皮性卵巢癌的成像技術。（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.
