Noske Aurelia, Henricksen Leigh A, LaFleur Bonnie, Zimmermann Anne-Katrin, Tubbs Alisa, Singh Shalini, Storz Martina, Fink Daniel, Moch Holger
Institute of Surgical Pathology, University Hospital Zurich, Schmelzbergstr. 12, CH-8091 Zurich, Switzerland.
Ventana Medical Systems, Inc., 1910 East Innovation Park Drive, Tucson, AZ 85755, USA.
Exp Mol Pathol. 2015 Feb;98(1):47-54. doi: 10.1016/j.yexmp.2014.12.004. Epub 2014 Dec 16.
CCNE1 is frequently amplified in high grade serous ovarian cancer and may serve as a target for ovarian cancer treatment. URI is closely related to CCNE1 at the 19q12 amplicon and may also contribute to the oncogenic effect. Our objective was to investigate the relevance of CCNE1 and URI gene amplification and protein expression in different histological subtypes of epithelial ovarian cancer (EOC).
A novel dual-color 19q12 in situ hybridization (ISH), covering CCNE1 and URI, and chromosome 19 as a surrogate using Ventana BenchMark XT platform was developed and applied to 148 EOCs. URI and CCNE1 amplifications were separately assessed by fluorescence in situ hybridization (FISH). Immunohistochemistry using a Cyclin E1 and a novel URI monoclonal antibody was performed.
Amplification of 19q12 was found in 36.6%, CCNE1 in 21.7%, URI in 9.9%, and both genes simultaneously in 9% of EOC cases. High Cyclin E1 and URI protein expression were observed in 52.2% and 26.1%, respectively. Amplification of 19q12 occurred in all EOC subtypes and was associated with amplification and expression of CCNE1/Cyclin E1, URI, TP53 mutation, and advanced stage.
The novel 19q12 ISH probe reliably detects both CCNE1 and URI amplifications as confirmed by FISH. The combination of 19q12 amplification with Cyclin E1 and URI protein expression may help to select patients more likely to benefit from CDK2 targeted therapies.
CCNE1在高级别浆液性卵巢癌中经常扩增，可能作为卵巢癌治疗的靶点。URI在19q12扩增子处与CCNE1密切相关，也可能促成致癌作用。我们的目的是研究CCNE1和URI基因扩增及蛋白表达在不同组织学亚型上皮性卵巢癌（EOC）中的相关性。
开发了一种新型双色19q12原位杂交（ISH），覆盖CCNE1和URI，并以19号染色体作为替代，使用Ventana BenchMark XT平台，应用于148例EOC。通过荧光原位杂交（FISH）分别评估URI和CCNE1的扩增情况。使用细胞周期蛋白E1和一种新型URI单克隆抗体进行免疫组织化学检测。
在36.6%的EOC病例中发现19q12扩增，21.7%发现CCNE1扩增，9.9%发现URI扩增，9%的病例同时发现两个基因扩增。分别在52.2%和26.1%的病例中观察到高细胞周期蛋白E1和URI蛋白表达。19q12扩增发生在所有EOC亚型中，并与CCNE1/细胞周期蛋白E1、URI的扩增和表达、TP53突变及晚期相关。
如FISH所证实，新型19q12 ISH探针可可靠地检测CCNE1和URI扩增。19q12扩增与细胞周期蛋白E1和URI蛋白表达相结合，可能有助于选择更可能从CDK2靶向治疗中获益的患者。
