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2 Heterogeneous chromosomal profiles in a unique series of DIPG in children and young adults European Congress of Pathology Amsterdam, 6 th September 2017 Charlotte Dufour, Romain Vasseur, Romain Perbet, Pierre Leblond, Matthieu Vinchon, Nicolas Reyns, Gustavo Touzet, Claude-Alain Maurage, Florence Renaud, Fabienne Escande
3 A brief introduction Diffuse Intrinsic Pontine Gliomas Arise almost exclusively in children and young adults Aggressive tumors with medial survival < 1 year Surgical removal impossible, no effective treatment Failure of 250 clinical trials [1] Diagnostic biopsy not systematically performed Improvement of stereotactic biopsy, safe procedure [2] Molecular characterization of this entity [1] Lapin et al, Frontiers in Oncology, 2017 [2] Puget et al, Childs Nerv Syst, 2015
4 K28M histone H3 mutations K28M H % H3F3A (Chr 1) % of DIPG [3] K28M H % Mostly HIST1H3B WILD TYPE H3 K28M H3.2 [4] (HIST2H3C) K27I H3.3 [4] Loss of trimethylation (IHC) Poorer prognosis WHO 2016: DIFFUSE MIDLINE GLIOMA, H3 K27M mutant, grade IV including DIPG [3] Buczkowicz P, Hawkins C, Frontiers in Oncology, 2015 [4] Castel et al, Acta Neuropathol, 2015
5 Other genomic alterations TP53 Mutation / Deletion (Chr 17) ACVR1 Mutation (Chr 2) PDGFRA Amplification (Chr 4) % of DIPG [3] % of DIPG [3] % of DIPG [3] More likely to occur with K28M H3.3 and WT H3 Significant association with K28M Significant association with histone H3.1 - Better outcome [5] H3 mutations [6] PIK3R1, PIK3CA mutation, MYC amplification What about chromosomal alterations? [5] Taylor et al, Nat Genet, 2014 [6] Buczkowicz et al, Nat Genet 2014
6 Patients and methods University Hospital of Lille (France) Children and young adults Neurological symptoms Tumour of the brainstem PRE-THERAPEUTIC STEREOTACTIC BIOPSY FROZEN and/or FFPE samples Histological study: diagnosis of diffuse glioma Grade (previous to WHO 2016)
7 Strategy 39 patients Mean age years (from 1 to 28) Brainstem diffuse glioma - Initially WHO grade II to grade IV MOLECULAR ANALYSES H3F3A HIST1H3B HIST1H3C HIST2H3C ACVR1 IDH1-2 BRAF (targeted next-generation sequencing) Fusion transcript (KIAA/BRAF) (RT-PCR) RECLASSIFICATION according to WHO 2016 CGH-array analysis CHROMOSOMAL ALTERATIONS SURVIVAL DATA
8 Results Pilocytic astrocytoma 4 2/ % Astrocytoma III GBM IV IDH-wildtype 3 9/36 25 % Astrocytoma II/III IDH-mutant Diffuse midline glioma IV H3 K27M-mutant 2 1 2/ % Histone H3 mutations 23/ % patients with non interpretable molecular data
9 Histone H3 mutants - Chromosomal alterations Loss Gain Amplification
10 Histone H3 mutants - Chromosomal alterations Q +2 PDGFRA -5Q -10Q -11Q -13Q -14Q -16Q -X
11 Results Pilocytic astrocytoma 4 2/ % Astrocytoma III GBM IV IDH-wildtype 3 9/36 25 % Astrocytoma II/III IDH-mutant Diffuse midline glioma IV H3 K27M-mutant 2 1 2/ % Histone H3 mutations 23/ % patients with non interpretable molecular data
12 Histone H3 mutants VS Wild-type Histone H3 mutants Wild-type
13 Histone H3 mutants - Pejorative alterations 1 1 0,9 0,8 PDGFRA NO 0,9 0,8 11q NO 0,7 0,6 0,7 p = 0.01 p = ,6 0,5 0,5 0,4 0,4 0,3 0,3 0,2 0,2 0,1 0, Time (months) Time (months) PDGFRA amplification Loss of 11q NO SIGNIFICATIVE DIFFERENCE for +1q, -5q, -10q, -13q, -14q, -16q, -X
14 Conclusion Our study Large series, exhaustive study of chromosomal alterations with pre-therapeutic samples Diffuse Intrinsic Pontine Gliomas NOT ONLY histone H3 mutated gliomas Importance of molecular diagnosis (IDH, Histone H3, fusion transcript) PDGFRA amplification % in DIPG [8][9] [10] Association with H3.3 mutations? [4] Linked to a poorer outcome? [11] Interest of immunohistochemistry in routine diagnosis? Loss of 11q Novel description Already described: +1q/+2/+8q/+9q/-10q/ -11p/-14q/-17p/-18p/-22q [1] To be continued [8] Wu et al, Nat Gent, 2014 [9] Hoffman et al, Acta Neuropathol, 2016 [10] Buczkowicz et al, Acta Neuropathol, 2014 [11] Puget et al, Plos One, 2012
15 Heterogeneous chromosomal profiles in a unique series of DIPG in children and young adults Charlotte Dufour, Romain Vasseur, Romain Perbet, Pierre Leblond, Matthieu Vinchon, Nicolas Reyns, Gustavo Touzet, Claude-Alain Maurage, Florence Renaud, Fabienne Escande Acknowledgments
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