title: BRAF mutation is associated with a specific cell type with features suggestive of senescence in ovarian serous borderline (atypical proliferative) tumors.
abstract: Serous borderline tumor also known as atypical proliferative serous tumor (APST) is the precursor of ovarian low-grade serous carcinoma (LGSC). In this study, we correlated the morphologic and immunohistochemical phenotypes of 71 APSTs and 18 LGSCs with the mutational status of KRAS and BRAF, the most common molecular genetic changes in these neoplasms. A subset of cells characterized by abundant eosinophilic cytoplasm (EC), discrete cell borders, and bland nuclei was identified in all (100%) 25 BRAF-mutated APSTs but in only 5 (10%) of 46 APSTs without BRAF mutations (P<0.0001). Among the 18 LGSCs, EC cells were found in only 2, and both contained BRAF mutations. The EC cells were present admixed with cuboidal and columnar cells lining the papillae and appeared to be budding from the surface, resulting in individual cells and clusters of detached cells "floating" above the papillae. Immunohistochemistry showed that the EC cells always expressed p16, a senescence-associated marker, and had a significantly lower Ki-67 labeling index than adjacent cuboidal and columnar cells (P=0.02). In vitro studies supported the interpretation that these cells were undergoing senescence, as the same morphologic features could be reproduced in cultured epithelial cells by ectopic expression of BRAF(V600E). Senescence was further established by markers such as SA-β-gal staining, expression of p16 and p21, and reduction in DNA synthesis. In conclusion, this study sheds light on the pathogenesis of this unique group of ovarian tumors by showing that BRAF mutation is associated with cellular senescence and the presence of a specific cell type characterized by abundant EC. This "oncogene-induced senescence" phenotype may represent a mechanism that impedes progression of APSTs to LGSC.
authors.affiliation: Departments of *Pathology and Gynecology and Obstetrics #Oncology, Johns Hopkins Medical Institutions, Baltimore, MD ¶The Wistar Institute, Philadelphia, PA †Department of Gynecology and Obstetrics, University Hospital Aachen, Aachen, Germany ‡Unit of Virus, Lifestyle and Genes, Danish Cancer Society Research Center ∥Juliane Marie Centre, Rigshospitalet, University of Copenhagen, Copenhagen §Department of Pathology, Hvidovre Hospital, Denmark Gynecologic Clinic, Hvidovre, Denmark.
authors.forename: Felix
authors.initials: F
authors.lastname: Zeppernick
authors.forename: Laura
authors.initials: L
authors.lastname: Ardighieri
authors.forename: Charlotte G
authors.initials: CG
authors.lastname: Hannibal
authors.forename: Russell
authors.initials: R
authors.lastname: Vang
authors.forename: Jette
authors.initials: J
authors.lastname: Junge
authors.forename: Susanne K
authors.initials: SK
authors.lastname: Kjaer
authors.forename: Rugang
authors.initials: R
authors.lastname: Zhang
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kurman
authors.forename: Ie-Ming
authors.initials: IeM
authors.lastname: Shih
mesh_terms: D016922:Cellular Senescence / Q000235:genetics*; D018284:Cystadenocarcinoma, Serous / Q000235:genetics* / Q000473:pathology*; D018293:Cystadenoma, Serous / Q000235:genetics / Q000473:pathology; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins