MYCN amplification drives an aggressive form of spinal ependymoma

被引：135

作者：

Ghasemi, David R. ^{[1
,2
]}

Sill, Martin ^{[1
,2
]}

Okonechnikov, Konstantin ^{[1
,2
]}

Korshunov, Andrey ^{[3
,4
]}

Yip, Stephen ^{[5
]}

Schutz, Peter W. ^{[5
]}

Scheie, David ^{[6
]}

Kruse, Anders ^{[7
]}

Harter, Patrick N. ^{[8
,9
,10
]}

Kastelan, Marina ^{[11
,12
]}

Wagner, Marlies ^{[13
,14
]}

Hartmann, Christian ^{[15
]}

Benzel, Julia ^{[1
,2
]}

Maass, Kendra K. ^{[1
,2
,16
]}

Khasraw, Mustafa ^{[17
]}

Straeter, Ronald ^{[18
]}

Thomas, Christian ^{[19
]}

Paulus, Werner ^{[19
]}

Kratz, Christian P. ^{[20
]}

Witt, Hendrik ^{[1
,2
,16
]}

Kawauchi, Daisuke ^{[1
,2
]}

Herold-Mende, Christel ^{[21
]}

Sahm, Felix ^{[1
,3
,4
]}

Brandner, Sebastian ^{[22
,23
]}

Kool, Marcel ^{[1
,2
]}

Jones, David T. W. ^{[1
,24
]}

von Deimling, Andreas ^{[3
,4
]}

Pfister, Stefan M. ^{[1
,2
,16
]}

Reuss, David E. ^{[3
,4
]}

Pajtler, Kristian W. ^{[1
,2
,16
]}

机构：

[1] Hopp Childrens Canc Ctr Heidelberg KiTZ, Heidelberg, Germany

[2] German Canc Consortium DKTK, Div Pediat Neurooncol, German Canc Res Ctr DKFZ, Heidelberg, Germany

[3] German Consortium Translat Canc Res DKTK, Clin Cooperat Unit Neuropathol, German Canc Res Ctr DKFZ, Heidelberg, Germany

[4] Heidelberg Univ Hosp, Inst Pathol, Dept Neuropathol, Heidelberg, Germany

[5] Univ British Columbia, Pathol & Lab Med, Vancouver, BC, Canada

[6] Rigshosp, Dept Pathol, Copenhagen, Denmark

[7] Rigshosp, Dept Orthoped Surg, Spine Sect, Copenhagen, Denmark

[8] Goethe Univ, Univ Hosp Frankfurt, Inst Neurol, Edinger Inst, Frankfurt, Germany

[9] German Canc Consortium DKTK, German Canc Res Ctr DKFZ, Partner Site Frankfurt Mainz, Heidelberg, Germany

[10] FCI, Frankfurt, Germany

[11] Royal North Shore Hosp, Northern Sydney Canc Ctr, Sydney, NSW, Australia

[12] Brain Canc Grp, Sydney, NSW, Australia

[13] LOEWE Ctr Personalized Translat Epilepsy Res CePT, Frankfurt, Germany

[14] Goethe Univ Hosp Frankfurt, Inst Neuroradiol, Frankfurt, Germany

[15] Hannover Med Sch, Dept Neuropathol, Hannover, Germany

[16] Univ Hosp Heidelberg, Dept Pediat Oncol Hematol & Immunol, Heidelberg, Germany

[17] Univ Sydney, Royal North Shore Hosp, Sydney, NSW, Australia

[18] Univ Munster, Dept Pediat Hematol Oncol, Munster, Germany

[19] Univ Hosp Munster, Inst Neuropathol, Munster, Germany

[20] Hannover Med Sch, Dept Pediat Hematol & Oncol, Hannover, Germany

[21] Heidelberg Univ Hosp, Dept Neurosurg, Heidelberg, Germany

[22] Univ Coll London Hosp NHS Fdn Trust, Natl Hosp Neurol & Neurosurg, Div Neuropathol, London, England

[23] UCL, Dept Neurodegenerat Dis, Inst Neurol, Queen Sq, London, England

[24] German Canc Res Ctr, Pediat Glioma Res Grp, Heidelberg, Germany

来源：

ACTA NEUROPATHOLOGICA | 2019年 / 138卷 / 06期

基金：

英国医学研究理事会;

关键词：

Ependymoma; Intradural extramedullary ependymoma; MYCN; Spinal tumor; DNA methylation; CNS malignancies; INTRADURAL EXTRAMEDULLARY EPENDYMOMA; RADIOLOGIC-PATHOLOGICAL CORRELATION; CENTRAL-NERVOUS-SYSTEM; TARGETING MYCN; N-MYC; NEUROBLASTOMA; CLASSIFICATION; TUMORS; DIFFERENTIATION; COMPARTMENTS;

D O I：

10.1007/s00401-019-02056-2

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Spinal ependymal tumors form a histologically and molecularly heterogeneous group of tumors with generally good prognosis. However, their treatment can be challenging if infiltration of the spinal cord or dissemination throughout the central nervous system (CNS) occurs and, in these cases, clinical outcome remains poor. Here, we describe a new and relatively rare subgroup of spinal ependymal tumors identified using DNA methylation profiling that is distinct from other molecular subgroups of ependymoma. Copy number variation plots derived from DNA methylation arrays showed MYCN amplification as a characteristic genetic alteration in all cases of our cohort (n = 13), which was subsequently validated using fluorescence in situ hybridization. The histological diagnosis was anaplastic ependymoma (WHO Grade III) in ten cases and classic ependymoma (WHO Grade II) in three cases. Histological re-evaluation in five primary tumors and seven relapses showed characteristic histological features of ependymoma, namely pseudorosettes, GFAP- and EMA positivity. Electron microscopy revealed cilia, complex intercellular junctions and intermediate filaments in a representative sample. Taking these findings into account, we suggest to designate this molecular subgroup spinal ependymoma with MYCN amplification, SP-EPN-MYCN. SP-EPN-MYCN tumors showed distinct growth patterns with intradural, extramedullary localization mostly within the thoracic and cervical spine, diffuse leptomeningeal spread throughout the whole CNS and infiltrative invasion of the spinal cord. Dissemination was observed in 100% of cases. Despite high-intensity treatment, SP-EPN-MYCN showed significantly worse median progression free survival (PFS) (17 months) and median overall survival (OS) (87 months) than all other previously described molecular spinal ependymoma subgroups. OS and PFS were similar to supratentorial ependymoma with RELA-fusion (ST-EPN-RELA) and posterior fossa ependymoma A (PF-EPN-A), further highlighting the aggressiveness of this distinct new subgroup. We, therefore, propose to establish SP-EPN-MYCN as a new molecular subgroup in ependymoma and advocate for testing newly diagnosed spinal ependymal tumors for MYCN amplification.

引用

页码：1075 / 1089

页数：15

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