BRAF mutation is associated with a specific cell type with features suggestive of senescence in ovarian serous borderline (atypical proliferative) tumors.
BRAF mutation is associated with a specific cell type with features suggestive of senescence in ovarian serous borderline (atypical proliferative) tumors.
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DOI：
10.1097/pas.0000000000000313
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发表时间：
2014-12
期刊：
影响因子：
--
通讯作者：
Shih IeM
中科院分区：
文献类型：
--
作者：
Zeppernick F;Ardighieri L;Hannibal CG;Vang R;Junge J;Kjaer SK;Zhang R;Kurman RJ;Shih IeM
浆液性交界性肿瘤（SBT）也称为非典型增殖性浆液性肿瘤（APST），是卵巢低级别浆液性癌（LGSC）的前兆。在这项研究中，我们将 71 个 APST 和 18 个 LGSC 的形态学和免疫组织化学表型与 KRAS 和 BRAF 的突变状态（这些肿瘤中最常见的分子遗传变化）相关联。在所有 (100%) 25 个 BRAF 突变的 APST 中都鉴定出了以丰富的嗜酸性细胞质 (EC)、不连续的细胞边界和平淡的细胞核为特征的细胞子集，但在 46 个无 BRAF 突变的 APST 中只有 5 个 (10%) (p<0.0001)。在18个LGSC中，仅发现2个EC细胞，且均含有BRAF突变。 EC 细胞与乳头内衬的立方形和柱状细胞混合存在，并且似乎从表面出芽，导致单个细胞和分离细胞簇“漂浮”在乳头上方。免疫组织化学显示EC细胞始终表达p16（一种衰老相关标记），并且Ki-67标记指数显着低于邻近的立方形和柱状细胞（p=0.02）。体外研究支持这样的解释：这些细胞正在经历衰老，因为通过 BRAFV600E 的异位表达，可以在培养的上皮细胞中再现相同的形态特征。通过 SA-β-gal 染色、p16 和 p21 的表达以及 DNA 合成的减少等标记进一步确定了衰老。总之，这项研究通过表明 BRAF 突变与细胞衰老和以丰富的嗜酸性细胞质为特征的特定细胞类型的存在相关，揭示了这一独特卵巢肿瘤的发病机制。这种“癌基因诱导的衰老”表型可能代表了一种阻止 APST 进展为 LGSC 的机制。
Serous borderline tumor (SBT) 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 BRAFV600E. 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 eosinophilic cytoplasm. This “oncogene-induced senescence” phenotype may represent a mechanism that prevents impedes progression of APSTs to LGSC.