Genomic analysis of childhood tumors: Biological and therapeutic implications. Peter Lichter German Cancer Research Center, DKFZ
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1 Genomic analysis of childhood tumors: Biological and therapeutic implications Peter Lichter German Cancer Research Center, DKFZ
2 Disclosure Nothing to disclose Off-label use of drugs will be discussed
3 International Cancer Genome Consortium Heidelberg Center for Personalized Oncology (DKFZ-HIPO) > 90 ICGC Projects HIPO Heidelberg Center for Personalized Oncology Clinical Development HIPO gen Genome Analysis Program Peter Lichter HIPO sys Systems Biology Bioinforma cs Synthe c Biology Program Roland Eils Project Management & Coordina on HIPO med NCT Precision Oncology Program (NCT-POP) Christof v. Kalle Sample Processing Pfütze/Geörg Sequencing/ Arrays Wolf/Wiemann Bew.-Hudler Data Management J.Eils/Lawerenz Bioinforma cs R.Eils/Brors Chroma n- and RNA Methods Mallm/Rippe Next Genera on Imaging PedBrain Tumor (Pediatric Brain Technology Tumors) Pla orms WGS, n > 550 Mission: Transferring results of high-throughput next generation sequencing to clinical practice Conrad Proteomics => Pilocytic Astrocytoma, Medulloblastoma, Glioblastoma, Ependymoma N.N.
4 Pilocytic Astrocytoma n = 96 Novel actionable targets Alterations in one pathway in 100% of cases Pilocytic Astrocytoma: a single pathway disease! => Therapy options Jones et al. Nature Genetics 2013 David Jones
5 V600E From Preclinical candidate model genes towards preclinical models BRAF kinase domain Construct Incidence (tumors/dead) BRAF wt FL 0/10 BRAF V600E FL 0/10 BRAF wt Kin 0/10 BRAF V600E Kin 26/29 (89%) Pilocytic Astrocytoma Gronych et al., J Clin Invest, 2011 Currently used to test inhibitors of BRAF and other MAP kinase pathway factors
6 Patient example *2008, female 11/2013: initial diagnosis Anaplastic Astrocytoma (Grade III) treatment according to the standard protocol (radiotherapy & temozolomide) 11/2014: Tumor progress 12/2014: sequence analysis: FAM131B:BRAF fusion, typical for Pilocytic Astrocytoma (Grade I) => MAPK pathway activation Patient now treated with a MEK-inhibitor (Trametinib) + valproate + low-dose cyclophosphamide + chloroquine since 10/2015: stable disease Chromosome 7
7 Medulloblastoma: Molecular Classification Northcott et al. Nature Reviews Cancer 2012
8 Infants, children & adult SHH-MBs: different mutations in pathway infants ( 3) children (4 17) adults ( 18) somatic germline germline unknown amplification N = 133 no? yes infants SMO response? no? yes children Stefan Pfister no? yes adults Marcel Kool Kool et al., Cancer Cell 2014
9 SMO inhibition in different SHH models LDE-225, a drug already tested in clinical trials Rob Wechsler-Reya Kool et al., Cancer Cell 2014
10 Infants, children & adult SHH-MBs: different mutations in pathway infants ( 3) children (4 17) adults ( 18) somatic germline germline unknown amplification N = 133 Kool et al., Cancer Cell 2014 TP53 Mutations in SHH-Medulloblastoma are linked to chromothripsis and are germline mutations Chromothripsis Rausch et. al, Cell 2012 Clinical implications: no SMO-inhibitors minimize radiation genetic counseling
11 MB Landscape Study: WGS=241; WES=17 WGS=37 WGS=112 WES=84 Totals: 491 MB sequences WGS: 390 MB/germline pairs WES: 101 MB/germline pairs Northcott et al. Nature, in press
12 Landscape of driver genes & pathways underlying medulloblastoma Paul Northcott Ivo Buchhalter What can we learn from sequencing 500 MBs?: - identify cooperating genes & pathways in WNT-/SHH-driven subgroups - assign drivers to high proportion of unexplained Group 3 & Group 4 patients Northcott et al. Nature, in press
13 Recurrent SNVs/indels in MB subgroups Northcott et al. Nature, in press
14 Disruption of distinct chromatin modifying complexes in WNT & SHH medulloblastoma Histone acetyltransferase complex 19.1 % of SHH-Medulloblastoma SWI/SNF superfamily type complex 33.3 % of WNT-Medulloblastoma Northcott et al. Nature, in press Tobi Ehrenberger & Ernest Fraenkel (MIT)
15 Driver events now explain >75-80% of Group 3 & 4 medulloblastoma Northcott et al. Nature, in press
16 Systematic enhancer hijacking analysis identifies PRDM6 in Group 4 medulloblastoma > 17 % of cases Northcott et al Nature, 511: Joachim Weischenfeldt (EMBL) Northcott et al. Nature, in press
17 SNCAIP-associated SVs disrupt local chromatin neighbourhoods to activate PRDM6 Northcott et al. Nature, in press TAD: Topologically associating domain Activation of a SET-domain protein (putative histonelysine-methyltransferase)
![Glioblastoma ICGC-ID Age [years] 24 16 13 18 7 11 x 8 27 5 NY 6 x 28 4 5 8 5 13 8 13 14 15 19 19 30 31 25 16](/docs-images/93/111971022/images/18-4.jpg "27 12 6 1 12 15 17 5 4 12 13 7 1 7 8 4 7 7 4 20 12 14 9 NY 7 19 16 14 Location H3F3A IDH1/2 ATRX SETD1A")
18 ICGC_GBM2 ICGC_GBM12 ICGC_GBM16 ICGC_GBM17 ICGC_GBM18 ICGC_GBM24 ICGC_GBM26 ICGC_GBM27 ICGC_GBM33 ICGC_GBM53 ICGC_GBM60 ICGC_GBM66 ICGC_GBM80 ICGC_GBM7 ICGC_GBM28 ICGC_GBM31 ICGC_GBM38 ICGC_GBM65 ICGC_GBM74 INF_51_XT1 ICGC_GBM5 ICGC_GBM22 ICGC_GBM39 ICGC_GBM42 ICGC_GBM43 ICGC_GBM44 ICGC_GBM45 ICGC_GBM62 ICGC_GBM73 ICGC_GBM79 ICGC_GBM1 ICGC_GBM4 ICGC_GBM9 ICGC_GBM11 ICGC_GBM14 ICGC_GBM15 ICGC_GBM19 ICGC_GBM21 ICGC_GBM23 ICGC_GBM25 ICGC_GBM32 ICGC_GBM34 ICGC_GBM36 ICGC_GBM40 ICGC_GBM41 ICGC_GBM46 ICGC_GBM49 ICGC_GBM52 ICGC_GBM54 ICGC_GBM56 ICGC_GBM57 ICGC_GBM58 ICGC_GBM59 ICGC_GBM61 ICGC_GBM63 ICGC_GBM67 ICGC_GBM71 Sequencing of 55 Pediatric Glioblastoma ICGC-ID Age [years] x NY 6 x NY Location H3F3A IDH1/2 ATRX SETD1A MYC/MYCN BRAF EGFR FGFR1-4 KIT MAPK1 MET MTOR NF1 NRAS/KRAS NTRK1-3 PDGFRA PIK3CA PIK3R1/2 PTEN MSH6 CDKN2A/B TP53/PPM1D RB1 RNAseq showed recurrent fusions involving MET David Jones Sebastian Bender Bender et al., Nature Medicine 2016
19 Mouse model: MET fusion causative for glioblastoma Jan Gronych Bender et al., Nature Med 2016
20 Fraction survival Preclinical testing of targeting inhibitors Survival of Foretinib 60mg/kg 1on1off Treatment 1.0 STOP 0.5 Foretinib Vehicle Days Bender et al., Nature Med 2016
21 Patient example *2006, male 04/2011: initial diagnosis of a metastasized group 3 Medulloblastoma treatment according to the standard protocol (incl. craniospinal irradiation) 09/2014: massive tumor growth 10/2014: sequence analysis: PTPRZ1-MET fusion with amplification and overexpression of MET + TP53 mutation (most likely radiation-induced Glioblastoma) MET PTPRZ1 Chr 7
22 Patient example: Treatment response.. and resistance? Treatment with a MET-inhibitor (Crizotinib) baseline post-op 2 months Crizotinib further 16 days Crizotinib
23 INFORM: next-generation diagnostics for children with progressive/relapsed malignancies Stefan Pfister Peter Lichter Angelika Eggert Olaf Witt INFORM
24 INFORM Identification of actionable targets by NGS => molecular tumor board => targeted therapy approaches Pilot Phase Registry Study (feasibility year 1+2, continued) Clinical trials INFORM2 treatment arms (phase I/II) ITCC ESMART Other phase I/II trials 10/21/ /19/2015 Q INFORM
25 Summary Pilocytic astrocytoma: a single pathway disease, MEK-Inhibitors are tested Medulloblastoma: Detailed pathway considerations required High rate of inherited predisposition => specific recommendations for counseling Large study revealed novel pathogenic mechanisms chromatin modifying complexes, hijacked enhancers Glioblastoma: Novel recurrent fusion gene, MET-Inhibitors => Clinical trials to meet problems of resistance by combinatorial treatment schemes => INFORM
26 Acknowledgements David Jones Andrey Korshunov Marcel Kool Paul Northcott Serap Erkek Natalie Jäger Roland Eils Matthias Schlesner Ivo Buchhalter Kortine Kleinheinz Benedikt Brors Dominik Sturm Sebastian Bender Stefan Pfister Olaf Witt, Till Milde Barbara Worst Aurélie Ernst Mansai Ratnaparkhe Kendra Maass Thorsten Kolb Agata Rode Volker Hovestadt Jan Gronych Marc Zapatka Marc Zuckermann Stephan Wolf & Core Facility Collaborators Andreas v. Deimling (Heidelberg) Jan Korbel (EMBL) Joachim Weischenfeldt (EMBL) Thomas Zichner (EMBL) Maia Segura-Wang (EMBL) Sebastian Waszak (EMBL) Rob Wechsler-Reya (San Diego) Michael D. Taylor (Toronto) Sorana Morrissy (Toronto) Marco Marra (Vancouver) Scott Pomeroy/Matthew Meyerson (Boston) Giles Robinson, Amar Gaijar (St, Judes, Memphis) Andreas E. Kulozik (Heidelberg) Christel Herold-Mende, Andreas Unterberg (Heidelberg) Marina Ryzhova (Moscow) Guido Reifenberger (Düsseldorf) Marie-Laure Yaspo, Thomas Risch, Hans-Joerg Warnatz (Berlin) Tobi Ehrenberger & Ernest Fraenkel (MIT)
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