Gousias Konstantinos, Niehusmann Pitt, Gielen Gerrit, Simon Matthias, Boström Jan
Department of Neurosurgery, University Hospital of Bonn, Sigmund Freud Strasse 25, 53105 Bonn, Germany.
Department of Neuropathology, University Hospital of Bonn, Bonn, Germany.
J Clin Neurosci. 2014 Oct;21(10):1719-24. doi: 10.1016/j.jocn.2014.01.011. Epub 2014 Jun 11.
The family of karyopherins comprises importins and exportins which are both involved in nucleocytoplasmic shuttling. Increased levels of karyopherin a2/importin 1 (KPNA2) and chromosome region maintenance protein 1/exportin 1 (CRM1) have been associated with poorer prognosis in patients with infiltrative astrocytomas. Isocitrate dehydrogenase 1 gene (IDH1) R132H mutation status was also recently identified as a prognostic factor for malignant gliomas. We evaluated KPNA2 and CRM1, as well as the IDH1 mutation status, as possible novel biomarkers for World Health Organization grade III anaplastic oligoastrocytomas (AOA). We analyzed nuclear expression of KPNA2 by immunohistochemistry in 72 primary anaplastic gliomas (29 AOA, 24 anaplastic astrocytomas, 19 anaplastic oligodendrogliomas). The IDH1 mutation status was also determined in patients with anaplastic astrocytomas and AOA, and AOA patients were additionally evaluated for CRM1 nuclear expression. Long term survivors (LTS; >8 years) with AOA showed lower KPNA2 expression levels compared to non-LTS (p=0.005). KPNA2 expression (⩾ 5% versus <5%, 1-<5%, median) was found to correlate inversely with overall survival (OS) and progression-free survival (PFS) in our overall series as well as in the AOA group (anaplastic gliomas: OS p=0.017; PFS p=0.033; AOA: OS p=0.017, PFS p=0.040). Mutant IDH1-R132H was detected in 69% of the AOA cohort; a combination of KPNA2 low expression and mutant IDH1-R132H was only seen in LTS (p=0.050). No differences between the histological subtypes were observed in terms of KPNA2 expression and IDH1-R132H mutation status. To our knowledge this is the first time it has been shown that KPNA2 expression may have potential as a prognostic biomarker for AOA as well.
核转运蛋白家族包括输入蛋白和输出蛋白，它们都参与核质穿梭。核转运蛋白α2/输入蛋白1（KPNA2）和染色体区域维持蛋白1/输出蛋白1（CRM1）水平升高与浸润性星形细胞瘤患者的预后较差相关。异柠檬酸脱氢酶1基因（IDH1）R132H突变状态最近也被确定为恶性胶质瘤的一个预后因素。我们评估了KPNA2和CRM1以及IDH1突变状态，作为世界卫生组织III级间变性少突星形细胞瘤（AOA）可能的新型生物标志物。我们通过免疫组织化学分析了72例原发性间变性胶质瘤（29例AOA、24例间变性星形细胞瘤、19例间变性少突胶质细胞瘤）中KPNA2的核表达。还确定了间变性星形细胞瘤和AOA患者的IDH1突变状态，并对AOA患者额外评估了CRM1的核表达。与非长期存活者相比，AOA的长期存活者（LTS；>8年）显示出较低的KPNA2表达水平（p = 0.005）。在我们的整个系列以及AOA组中，发现KPNA2表达（⩾5%与<5%、1 - <5%、中位数）与总生存期（OS）和无进展生存期（PFS）呈负相关（间变性胶质瘤：OS p = 0.017；PFS p = 0.033；AOA：OS p = 0.017，PFS p = 0.040）。在69%的AOA队列中检测到突变型IDH1 - R132H；仅在LTS中观察到KPNA2低表达和突变型IDH1 - R132H的组合（p = 0.050）。在KPNA2表达和IDH1 - R132H突变状态方面，未观察到组织学亚型之间的差异。据我们所知，这是首次表明KPNA2表达也可能具有作为AOA预后生物标志物的潜力。
