Deep sequencing of a recurrent oligodendroglioma and the derived xenografts reveals new insights into the evolution of human oligodendroglioma and candidate driver genes

// Nadin D. Exner 1 , 2 , Jaime Alberto Campos Valenzuela 3 , Khalil Abou-El-Ardat 1 , Hrvoje Miletic 4 , 5 , Peter C. Huszthy 6 , Petra M. Radehaus 2 , Evelin Schrock 1 , 7 , 8 , 9 , Rolf Bjerkvig 5 , 10 , Lars Kaderali 11 , Barbara Klink 1 , 7 , 8 , 9 , 12 , * and Janice M. Nigro 5 , * 1 Institut fur Klinische Genetik, Medizinische Fakultat Carl Gustav Carus, Technische Universitat Dresden, Dresden, Germany 2 University of Applied Sciences Mittweida, Department of Applied Informatics & Biosciences, Mittweida, Germany 3 Institut fur Medizinische Informatik und Biometrie, Medizinische Fakultat Carl Gustav Carus, Technische Universitat Dresden, Dresden, Germany 4 Department of Pathology, Haukeland University Hospital, Bergen, Norway 5 Department of Biomedicine, University of Bergen, Bergen, Norway 6 Oslo University Hospital-Rikshospitalet, Department of Immunology, Oslo, Norway 7 German Cancer Consortium (DKTK), Dresden, Germany 8 German Cancer Research Center (DKFZ), Heidelberg, Germany 9 Center for Molecular Tumor Diagnostics, National Center for Tumor Diseases (NCT), Dresden, Germany 10 Oncology Department, Luxembourg Institute of Health, Val Fleuri, Luxembourg 11 University Medicine Greifswald, Institute of Bioinformatics, Greifswald, Germany 12 Centre national de Genetique, Laboratoire National de Sante, Dudelange, Luxembourg * Co-senior authors Correspondence to: Nadin D. Exner, email: nexner@mail.de Keywords: exome sequencing; IDH1; oligodendroglioma; SNV; xenograft Received: December 18, 2018     Accepted: May 04, 2019     Published: June 04, 2019 ABSTRACT We previously reported the establishment of a rare xenograft derived from a recurrent oligodendroglioma with 1p/19q codeletion. Here, we analyzed in detail the exome sequencing datasets from the recurrent oligodendroglioma (WHO grade III, recurrent O 2010 ) and the first-generation xenograft (xenograft 1 ). Somatic SNVs and small InDels ( n = 80) with potential effects at the protein level in recurrent O 2010 included variants in IDH1 (NM_005896:c.395G>A; p. Arg132His), FUBP1 (NM_003902:c.1307_1310delTAGA; p.Ile436fs), and CIC (NM_015125:c.4421T>G; p.Val1474Gly). All but 2 of these 80 variants were also present in xenograft 1 , along with 7 new variants. Deep sequencing of the 87 SNVs and InDels in the original tumor (WHO grade III, primary O 2005 ) and in a second-generation xenograft (xenograft 2 ) revealed that only 11 variants, including IDH1 (NM_005896:c.395G>A; p. Arg132His), PSKH1 (NM_006742.2:c.650G>A; p.Arg217Gln), and SNX12 (NM_001256188:c.470G>A; p.Arg157His), along with a variant in the TERT promoter (C250T, NM_198253.2: c.-146G>A), were already present in primary O 2005 . Allele frequencies of the 11 variants were calculated to assess their potential as putative driver genes. A missense change in NDST4 (NM_022569:c.2392C>G; p.Leu798Val) on 4q exhibited an increasing allele frequency (~ 20%, primary O 2005 , 80%, recurrent O 2010 and 100%, xenograft 1 ), consistent with a selection event. Sequencing of NDST4 in a cohort of 15 oligodendrogliomas, however, revealed no additional cases with potential protein disrupting variants. Our analysis illuminated a tumor evolutionary series of events, which included 1p/19q codeletion, IDH1 R132H, and TERT C250T as early events, followed by loss of function of NDST4 and mutations in FUBP1 and CIC as late events.