19q12 amplified and non-amplified subsets of high grade serous ovarian cancer with overexpression of cyclin E1 differ in their molecular drivers and clinical outcomes
19q12 amplified and non-amplified subsets of high grade serous ovarian cancer with overexpression of cyclin E1 differ in their molecular drivers and clinical outcomes
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DOI：
10.1016/j.ygyno.2018.08.039
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发表时间：
2018-11-01
影响因子：
4.7
通讯作者：
Waring, Paul
中科院分区：
文献类型：
--
作者：
Aziz, Diar;Etemadmoghadam, Dariush;Waring, Paul
目标.在50%的HGSOC中容易出现明显的细胞周期蛋白El表达，但只有一半与19q12基因座扩增有关。扩增的/细胞周期蛋白E1（hi）亚群具有完整的BRCA 1/2，不利的结果，并且是潜在的治疗靶向的。我们研究了非扩增/细胞周期蛋白E1（hi）HGSOC是否具有相似的特征。我们还评估了细胞周期蛋白El降解相关蛋白FBXW7和USP 28的表达，作为两个亚群中细胞周期蛋白El高表达的潜在驱动因素。应用原位杂交和免疫组化方法检测262例HGSOC中19q12基因座扩增和cyclin E1、URI1（19812基因座编码的另一种蛋白）、FBXW7和USP 28的表达。根据19q1/2扩增状态对肿瘤进行分类，并与细胞周期蛋白El和URI 1表达、BRCA 1/2生殖系突变、FBXW7和USP 28表达以及临床结果相关。此外，我们评估了来自癌症基因组数据库的HGSOC数据集的扩增/细胞周期蛋白E1（hi）和非扩增/细胞周期蛋白E1（hi）组的相对基因组不稳定性。在82例细胞周期蛋白El hi病例中，43例（52%）扩增，39例（48%）未扩增。与扩增肿瘤不同，非扩增/细胞周期蛋白E1（hi）肿瘤状态与gBRCA 1/2突变并不相互排斥。非扩增/细胞周期蛋白E1（hi）组具有显著增加的USP 28，而扩增/细胞周期蛋白E1（hi）癌症具有显著降低的FBXW7表达，这与两者在稳定细胞周期蛋白E1中的作用一致。值得注意的是，只有扩增的/细胞周期蛋白E1（hi）亚群与基因组不稳定性相关，其结果比非扩增的/细胞周期蛋白E1（hi）亚群更差。扩增型/细胞周期蛋白E1（hi）和非扩增型/细胞周期蛋白E1（hi）肿瘤具有不同的病理学和生物学特征以及临床结果，表明它们是细胞周期蛋白E1（hi）HGSOC的独立子集。(C)2018由Elsevier Inc.出版
Objectives. Readily apparent cyclin El expression occurs in 50% of HGSOC, but only half are linked to 19q12 locus amplification. The amplified/cyclin E1(hi) to subset has intact BRCA1/2, unfavorable outcome, and is potentially therapeutically targetable. We studied whether non-amplified/cyclin E1(hi) HGSOC has similar characteristics. We also assessed the expression of cyclin El degradation-associated proteins, FBXW7 and USP28, as potential drivers of high cyclin El expression in both subsets.Methods. 262 HGSOC cases were analyzed by in situ hybridization for 19q12 locus amplification and immunohistochemistry for cyclin El, URI1 (another protein encoded by the 19812 locus), FBXW7 and USP28 expression. Tumors were classified by 19q12 amplification status and correlated to cyclin El and URI1 expression, BRCA1/2 germline mutation, FBXW7 and USP28 expression, and clinical outcomes. Additionally, we assessed the relative genomic instability of amplified/cyclin E1(hi) and non-amplified/cyclin E1(hi) groups of HGSOC datasets from The Cancer Genome Atlas.Results. Of the 82 cyclin El hi cases, 43 (52%) were amplified and 39 (48%) were non-amplified. Unlike amplified tumors, non-amplified/cyclin E1(hi) tumor status was not mutually exclusive with gBRCA1/2 mutation. The non-amplified/cyclin E1(hi) group had significantly increased USP28, while the amplified/cyclin E1(hi) cancers had significantly lower FBXW7 expression consistent with a role for both in stabilizing cyclin E1. Notably, only the amplified/cyclin E1(hi) subset was associated with genomic instability and had a worse outcome than nonamplified/cyclin E1(hi) group.Conclusions. Amplified/cyclin E1(hi) and non-amplified/cyclin E1(hi) tumors have different pathological and biological characteristics and clinical outcomes indicating that they are separate subsets of cyclin E1(hi) HGSOC. (C) 2018 Published by Elsevier Inc.