Activation of the basal cell carcinoma pathway in a patient with CNS HGNET-BCOR diagnosis: consequences for personalized targeted therapy.
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.
Section of Pediatric Oncology, Children's Hospital, University Medical Center of The Johannes Gutenberg University Mainz, Germany.
Claudia
C
Paret
Section of Pediatric Oncology, Children's Hospital, University Medical Center of The Johannes Gutenberg University Mainz, Germany.
Johanna
J
Theruvath
Section of Pediatric Oncology, Children's Hospital, University Medical Center of The Johannes Gutenberg University Mainz, Germany.
Alexandra
A
Russo
Section of Pediatric Oncology, Children's Hospital, University Medical Center of The Johannes Gutenberg University Mainz, Germany.
Bettina
B
Kron
Section of Pediatric Oncology, Children's Hospital, University Medical Center of The Johannes Gutenberg University Mainz, Germany.
Khalifa
K
El Malki
Section of Pediatric Oncology, Children's Hospital, University Medical Center of The Johannes Gutenberg University Mainz, Germany.
Nadine
N
Lehmann
Section of Pediatric Oncology, Children's Hospital, University Medical Center of The Johannes Gutenberg University Mainz, Germany.
Arthur
A
Wingerter
Section of Pediatric Oncology, Children's Hospital, University Medical Center of The Johannes Gutenberg University Mainz, Germany.
Marie A
MA
Neu
Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center of The Johannes Gutenberg University Mainz, Germany.
Aslihan
A
Gerhold-Ay
Section of Pediatric Neurosurgery, Department of Neurosurgery, University Medical Center of The Johannes Gutenberg University Mainz, Germany.
Wolfgang
W
Wagner
Institute of Neuropathology, University Medical Center of The Johannes Gutenberg University Mainz, Germany.
Clemens
C
Sommer
Department of Neuropathology, University of Bonn, Germany.
Torsten
T
Pietsch
Institute of Pathology, University Medical Center of The Johannes Gutenberg University Mainz, Germany.
Larissa
L
Seidmann
Section of Pediatric Oncology, Children's Hospital, University Medical Center of The Johannes Gutenberg University Mainz, Germany.
Jörg
J
Faber
D000970:Antineoplastic Agents / Q000494:pharmacology; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D060466:Axin Protein / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001706:Biopsy; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002280:Basal Cell Carcinoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D004252:DNA Mutational Analysis; D004305:Dose-Response Relationship, Drug; D020022:Genetic Predisposition to Disease; D053823:Hedgehog Proteins / Q000235:genetics; D006801:Humans; D020128:Inhibitory Concentration 50; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D018302:Neoplasms, Neuroepithelial / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D010087:Oxides / Q000494:pharmacology; D000072081:Patched-1 Receptor / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D057285:Precision Medicine; D011237:Predictive Value of Tests; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D000072086:Smoothened Receptor / Q000235:genetics; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D060449:Wnt Signaling Pathway / Q000235:genetics; D000071676:Zinc Finger Protein GLI1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
C491761:AXIN2 protein, human; D000970:Antineoplastic Agents; D001152:Arsenicals; D060466:Axin Protein; C411984:BCOR protein, human; D014408:Biomarkers, Tumor; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D010087:Oxides; C000606236:PTCH1 protein, human; D000072081:Patched-1 Receptor; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C509239:SHH protein, human; C491023:SMO protein, human; C490764:SUFU protein, human; D000072086:Smoothened Receptor; D000071676:Zinc Finger Protein GLI1; D000077237:Arsenic Trioxide
AXIN; BCOR; GLI; HGNET-BCOR; WNT