Abstract 1424: KCNJ2 comprises a marker of poor prognosis and a therapeutic target in non-WNT/non-SHH medulloblastoma
Authors: Francesca Valdora, Florian Freier, Claudia Seyler, Nathan Brady, Dominique Kranz, Thomas Hielscher, Sebastian Bender, Paul Northcott, Marcel Kool, David Jones, Hendrik Witt, Marina Ryzhova, Sabrina Pleier, Simona Coco, Gian Paolo Tonini, Axel Benner, Andreas von Deimling, Wolfram Scheurlen, Michael Boutros, Michael Taylor, Hugo Katus, Andreas Kulozik, Peter Lichter, Andrey Korshunov, Edgar Zitron, Stefan Pfister, Marc Remke
Journal: Cancer Research (2012)

Abstract Medulloblastoma comprises the most common malignant brain tumor in childhood. Recently, integrated genomic approaches revealed four major biological disease variants: WNT (wingless), SHH (sonic hedgehog), group 3, and group 4. Treatment failure mainly occurs in children harboring metastatic tumors, which typically carry an isochromosome 17 or gain of 17q, a common hallmark of intermediate and high-risk non-WNT/non-SHH medulloblastoma. Thus, novel therapeutic options for these patients are urgently warranted. Through mRNA expression profiling of 64 primary tumor samples, we identified potassium inwardly-rectifying channel J2 (KCNJ2) as one of the most upregulated genes on chromosome 17q in tumors with 17q gain. Notably, recent reports have linked deregulation of voltage-dependent ion channels to the development of other types of cancer. We first validated our microarray findings on KCNJ2 transcript levels using quantitative real-time PCR. High KCNJ2 transcript levels were significantly associated with non-WNT/non-SHH grouping, anaplastic histology, metastatic dissemination, and poor clinical outcome. KCNJ2 protein expression was analyzed by immunohistochemistry in a large cohort of patients (n=199), and high protein expression levels were found to be strongly correlated with 17q gain, metastatic dissemination, and inferior overall and progression-free survival (p&amp;lt;0.0001). To functionally validate the potential role of KCNJ2 in medulloblastoma biology, we performed knockdown experiments by small interfering RNA-mediated silencing in two well characterized medulloblastoma cell lines. Knockdown of KCNJ2 resulted in a reduced proliferation rate and induction of apoptosis. Furthermore, treatment of the medulloblastoma cell lines with Amiodarone and SR 59230A, two inhibitors of this class of Kir channels, phenocopied these promising anti-proliferative and pro-apoptotic effects in a time- and dose-dependent manner. Whole cell patch clamp results revealed a remarkable current reduction upon inhibitor treatment with SR 59230A. In summary, we could delineate KCNJ2 immunopositivity as an independent biomarker for medulloblastoma with dismal prognosis. Thus, pharmacological inhibition of this candidate gene may constitute a new therapeutic option for patients with high-risk medulloblastomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1424. doi:1538-7445.AM2012-1424