Molecular Profiling Reclassifies Adult Astroblastoma into Known and Clinically Distinct Tumor Entities with Frequent Mitogen-Activated Protein Kinase Pathway Alterations William Boisseau, Philipp Euskirchen, Karima Mokhtari, Caroline Dehais, Mehdi Touat, Khê Hoang-Xuan, Marc Sanson, Laurent Capelle, Aurélien Nouet, Carine Karachi, et al. To cite this version: William Boisseau, Philipp Euskirchen, Karima Mokhtari, Caroline Dehais, Mehdi Touat, et al.. Molec- ular Profiling Reclassifies Adult Astroblastoma into Known and Clinically Distinct Tumor Entities with Frequent Mitogen-Activated Protein Kinase Pathway Alterations. Oncologist, AlphaMed Press, In press, 10.1634/theoncologist.2019-0223. hal-02291232 HAL Id: hal-02291232 https://hal.sorbonne-universite.fr/hal-02291232 Submitted on 18 Sep 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. 1 Molecular profiling reclassifies adult astroblastoma into known and 2 clinically distinct tumor entities with frequent MAPK pathway alterations 3 William Boisseau1* MD, Philipp Euskirchen2,3,4,5,6* MD, Karima Mokhtari3, 7 MD, Caroline 4 Dehais1 MD, Mehdi Touat3 MD, Khê Hoang-Xuan3 MD, PhD, Marc Sanson3 MD, PhD, 5 Laurent Capelle8 MD, Aurélien Nouet8 MD, Carine Karachi8 MD, Franck Bielle7 MD, PhD, 6 Justine Guégan3 MSc, Yannick Marie3 PhD, Nadine Martin Duverneuil9 MD, Luc 7 Taillandier10 MD, PhD, Audrey Rousseau11 MD, PhD, Jean-Yves Delattre3 MD, Ahmed 8 Idbaih3 MD, PhD 9 * both authors contributed equally to this study 10 1AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2- 11 Mazarin, F-75013, Paris, France. 12 2Dept. of Neurology, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany 13 3Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle 14 épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de 15 Neurologie 2-Mazarin, F-75013, Paris, France 16 4Berlin Institute of Health (BIH), 10178 Berlin, German 17 5German Cancer Consortium (DKTK), partner site Berlin 18 6German Cancer Research Center (DKFZ), Heidelberg, Germany 19 20 7AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de 21 Neuropathologie-Escourolle, F-75013, Paris, France. 22 8AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de 23 Neurochirurgie, F-75013, Paris, France. 24 9AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de 25 Neuroradiologie, F-75013, Paris, France. 26 10 Dept. Of Neurology, Centre Hospitalo-Universitaire de Nancy, Nancy, France 27 11Institut Cancérologique de l’Ouest Paul Papin, 15 rue André Boquel, 49055 Angers, France 28 29 Corresponding author 30 Dr Ahmed Idbaih 31 Department of Neurology 2-Mazarin, Hôpitaux Universitaires Pitié-Salpêtrière Charles Foix, 32 Assistance Publique Hôpitaux de Paris (APHP), Paris, France 33 47-83 Boulevard de l'Hôpital, 75013 Paris 34 Tel.: +33 1 42160385 35 Fax: +33 1 42160418 36 Email: [email protected] 37 38 39 40 41 42 Keywords: astroblastoma; next-generation sequencing; MN1-BEND2; BRAF mutation 43 44 Implications for Practice: 45 Astroblastoma (ABM) remains a poorly defined and controversial entity. While MN1 46 alterations seem to define a large subset of pediatric cases, adult cases remain molecularly 47 poorly defined. This comprehensive molecular characterization of 1 adolescent and 14 adult 48 ABM revealed that adult ABM histology comprises several molecularly defined entities, 49 which explains clinical diversity and identifies actionable targets. Namely, pleomorphic 50 xanthoastrocytoma (PXA)-like ABM case show a favorable prognosis while high-grade 51 gliomas (glioblastoma and diffuse midline gliome)-like ABM show significantly worse 52 clinical courses. Our results call for in-depth molecular analysis of adult gliomas with 53 astroblastic features for diagnostic and therapeutic purposes. 54 55 56 57 58 59 60 61 Abstract 62 63 Aims and methods: astroblastoma (ABM) is a rare glial brain tumor. Recurrent MN1 64 alterations have been recently identified in most pediatric cases. Adolescent and adult cases, 65 however, remain molecularly poorly defined. Here, we performed clinical and molecular 66 characterization of a retrospective cohort of 14 adult and one adolescent ABM. 67 Results: Strikingly, we found that MN1 fusions are a rare event in this age group (1/15). 68 Using methylation profiling and targeted sequencing, most cases were reclassified as either 69 pleomorphic xanthoastrocytomas (PXA)-like or high-grade glioma (HGG)-like. PXA-like 70 ABM show BRAF mutation (6/7 with V600E mutation and 1/7 with G466E mutation) and 71 CD34 expression. Conversely, HGG-like ABM harbored specific alterations of diffuse 72 midline glioma (2/5) or glioblastoma (3/5). These latter patients showed an unfavorable 73 clinical course with significantly shorter overall survival (p = 0.021). MAPK pathway 74 alterations (including FGFR fusion, BRAF and NF1 mutations) were present in 10 of 15 75 patients and overrepresented in the HGG-like group (3/5) compared to previously reported 76 prevalence of these alterations in GBM and diffuse midline glioma. 77 Conclusion: We suggest that gliomas with astroblastic features include a variety of 78 molecularly sharply defined entities. Adult ABM harboring molecular features of PXA and 79 HGG should be reclassified. CNS high-grade neuroepithelial tumors with MN1 alterations and 80 histology of ABM appear to be uncommon in adults. Astroblastic morphology in adults 81 should thus prompt thorough molecular investigation aiming at a clear histomolecular 82 diagnosis and identifying actionable drug targets, especially in the MAPK pathway. 83 84 85 86 87 Introduction 88 89 Astroblastoma (ABM) is a rare neuroepithelial tumor and has been recognized by the World 90 Health Organization (WHO) as a distinct tumor entity.1 It was first described in 1926 by 91 Bailey2 and further characterized by Bailey and Bucy3 in 1930. ABM is generally regarded as 92 an entity occuring in childern and young adults.4-6 However, in a recent epidemiological 93 survey, 56% of cases were diagnosed after 30 years of age.7 The diagnosis of ABM is based 94 on a typical histomorphology with perivascular astroblastic pseudorosettes and vascular 95 hyalinization2, 3, 8. However, perivascular arrangement of tumor cells is not specific for ABM 96 and may also be seen in other central nervous system tumors such as glioblastoma (GBM), 97 primitive neuroectodermal tumors (PNET), angiocentric glioma, and ependymomas.9, 10 The 98 lack of specific neuropathological features explains why the validity of ABM as a distinct 99 entity is still a matter of debate.11 100 Recently, efforts have been made to identify specific molecular alterations in ABM. In 2016, 101 Sturm and al12 have described a new molecularly defined tumor entity characterized by MN1 102 (meningioma 1) and BEND2 (BEN domain containing 2) fusion genes which histologically 103 frequently corresponds to ABM. Several reports have confirmed the existence of recurrent 104 MN1 alterations in pediatric and also adult ABM.13-15 In contrast, Lehman and colleagues16 105 showed that tumors with the histological diagnosis of ABM frequently harbor BRAF V600E 106 mutations. 107 Here, we report a comprehensive clinical, radiological, histological and molecular 108 characterization of a retrospective series of adolescent and adult ABM and show that they 109 share common clinical and molecular features with other glial tumor entities. 110 111 112 Material and Methods 113 114 Patient cohort and histological review 115 116 Patients were retrospectively identified using systematic archival review for the term 117 “astroblastoma” between 1990 and 2017 at the Pitié Salpêtrière university hospital, i.e. cases 118 with (i) a final diagnosis of astroblastoma or (ii) astroblastoma being mentioned in the 119 pathology report as a differential diagnosis. Tumors samples were stored with signed consent 120 form in the tumor tissue bank OncoNeuroTek. All identified cases were centrally reviewed by 121 experienced neuropathologists (KM and/or FB). Required histologic features for inclusion in 122 the study were: (i) the presence of perivascular astroblastic pseudorosettes; (ii) the presence of 123 hyalinized vessels; (iii) cuboidal, columnar, or tapered perivascular cellular processes, 124 occasionally ending in broad endfeet and (iv) absence of definitive criteria for other CNS 125 tumors. Hematoxylin and eosin staining as well as immunohistochemistry for Ki67, GFAP, 126 IDH1 R132H, ATRX, EMA, OLIG2, vimentin, FGFR3, H3K27M, p53 and NFkB 127 (commonly found in supratentorial ependymomas17) proteins were performed. Additional 128 immunohistochemical assessment of CD34 was done post-hoc on all cases with a confirmed 129 diagnosis of ABM. 130 131 Clinical and radiological data 132 133 For all patients, age at diagnosis, sex, clinical presentation, treatments and clinical outcome 134 were retrospectively collected. From initial diagnosis, progression free survival (PFS)