Activation of the basal cell carcinoma pathway in a patient with CNS HGNET-BCOR diagnosis: consequences for personalized targeted therapy
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Claudia Paret1,*, Johanna Theruvath1,*, Alexandra Russo1, Bettina Kron1, Khalifa El Malki1, Nadine Lehmann1, Arthur Wingerter1, Marie A. Neu1, Aslihan Gerhold-Ay2, Wolfgang Wagner3, Clemens Sommer4, Torsten Pietsch5, Larissa Seidmann6, Jörg Faber1
1Section of Pediatric Oncology, Children's Hospital, University Medical Center of The Johannes Gutenberg University Mainz, Germany
2Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center of The Johannes Gutenberg University Mainz, Germany
3Section of Pediatric Neurosurgery, Department of Neurosurgery, University Medical Center of The Johannes Gutenberg University Mainz, Germany
4Institute of Neuropathology, University Medical Center of The Johannes Gutenberg University Mainz, Germany
5Department of Neuropathology, University of Bonn, Germany
6Institute of Pathology, University Medical Center of The Johannes Gutenberg University Mainz, Germany
*These authors have contributed equally to the work
Claudia Paret, email: [email protected]
Keywords: HGNET-BCOR, BCOR, WNT, GLI, AXIN
Received: June 13, 2016 Accepted: October 19, 2016 Published: November 04, 2016
High grade neuroepithelial tumor of the central nervous system with BCOR alteration (CNS HGNET-BCOR) is a recently described new tumor entity with a dismal prognosis. The objective of this study was to identify and validate pathways deregulated in CNS HGNET-BCOR as basis for targeted therapy approaches.
We characterized the BCOR alteration in a pediatric patient with CNS HGNET-BCOR diagnosis by Sanger sequencing and demonstrated an elevated BCOR expression by qRT-PCR and western blot. By whole transcriptome sequencing and Ingenuity Pathway Analysis, we identified the activation of the Sonic Hedgehog (SHH) and of the WNT signaling pathway in two different regions of the primary tumor and of one inoculation metastasis compared to normal brain. We validated the activation of the SHH and of the WNT pathway by qRT-PCR analysis of GLI1 and AXIN2 respectively. GLI1 and AXIN2 were upregulated in the primary tumor and in two inoculation metastases compared to normal brain. Mutational analysis of SMO, PTCH1 and SUFU, three key components of the SHH pathway, revealed a Single Nucleotide Polymorphism (SNP) in PTCH1 (rs357564). We tested the effect of the GLI-inhibitor arsenic trioxide (ATO) on a short-term cell culture isolated from the metastasis. ATO was able to reduce the viability of the cells with an IC50 of 1.3 μM.
In summary, these results provide functional evidence of altered BCOR expression and homogeneous coactivation of both the SHH and WNT signaling pathways, building the basis for potential novel therapeutic approaches for patients with a CNS HGNET-BCOR diagnosis.
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