title: Comparative integrated molecular analysis of intraocular medulloepitheliomas and central nervous system embryonal tumors with multilayered rosettes confirms that they are distinct nosologic entities.
abstract: Intraocular medulloepithelioma (IO MEPL) is an uncommon embryonal neuroepithelial neoplasm of the eye. These ocular neoplasms have been compared with intracranial medulloepitheliomas or other histologic variants of CNS embryonal tumor with multilayered rosettes (CNS ETMR) due to their morphological mimicry. We performed comprehensive molecular analysis to explore the histogenetic and biologic relationships between 22 IO MEPL and 68 CNS ETMR. Routinely prepared paraffin-embedded samples were assessed for genome-wide methylation profiles using the Illumina Methylation 450k BeadChip array. We identified strong cytogenetic and epigenetic differences between ocular neoplasms and CNS ETMR. None of the IO MEPL cases displayed the ETMR-specific amplification of the C19MC locus. Instead, cytogenetic analysis of the IO MEPL showed numerous copy number aberrations which involved either whole chromosomes or chromosomal arms; recurrent aberrations in these tumors affected chromosomes 1p, 4, 8 and 16p. DNA methylation patterns were also strikingly different between these two tumor entities, suggesting that they do not share common origins and biological behaviors. Comparative cluster analysis of 198 pediatric CNS tumors and 22 IO MEPL revealed a clear demarcation of the CNS ETMR and IO MEPL profiles from other CNS entities. In conclusion, although IO MEPL shares some histopathological features with CNS ETMR, they manifest striking molecular diversity at the cytogenetic and epigenetic levels. Consequently they deserve a separate nosologic designation in future tumor classifications, where CNS MEPL could be designated as a histological variant of CNS ETMR.
authors.affiliation: Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), and Department of Neuropathology University Hospital, Heidelberg, Germany.|German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.affiliation: David G. Cogan Ophthalmic Pathology Laboratory, Massachusetts Eye & Ear Infirmary, Harvard Medical School, Boston, MA, USA.
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Jakobiec
authors.affiliation: John Hopkins University School of Medicine, Baltimore, MD, USA.|King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Hovestadt
authors.affiliation: Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), and Department of Neuropathology University Hospital, Heidelberg, Germany.|German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Capper
authors.affiliation: Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: David T W
authors.initials: DT
authors.lastname: Jones
authors.affiliation: Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Sturm
authors.affiliation: David G. Cogan Ophthalmic Pathology Laboratory, Massachusetts Eye & Ear Infirmary, Harvard Medical School, Boston, MA, USA.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Stagner
authors.affiliation: John Hopkins University School of Medicine, Baltimore, MD, USA.|King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.
authors.forename: Deepak P
authors.initials: DP
authors.lastname: Edward
authors.affiliation: Wills Eye Hospital, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Ralph C
authors.initials: RC
authors.lastname: Eagle
authors.affiliation: Department of Pathology, Duke University, Durham, NC, USA.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Proia
authors.affiliation: Institute for Neuropathology, Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Arend
authors.initials: A
authors.lastname: Koch
authors.affiliation: Department of Neuropathology, NN Burdenko Neurosurgical Institute, Moscow, Russia.
authors.forename: Marina
authors.initials: M
authors.lastname: Ryzhova
authors.affiliation: Department of Pathology, Russian Children's Clinical Hospital, Moscow, Russia.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Ektova
authors.affiliation: Center of Neuropathology, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schüller
authors.affiliation: Department of Neuro-Oncology, Russian Scientific Center of Radiology, Moscow, Russia.
authors.forename: Olga
authors.initials: O
authors.lastname: Zheludkova
authors.affiliation: German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.|Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Lichter
authors.affiliation: Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), and Department of Neuropathology University Hospital, Heidelberg, Germany.|German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.affiliation: German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.|Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.affiliation: Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kool
mesh_terms: D000293:Adolescent; D000328:Adult; D016543:Central Nervous System Neoplasms / Q000145:classification* / Q000235:genetics / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D016000:Cluster Analysis; D005134:Eye Neoplasms / Q000145:classification* / Q000235:genetics / Q000473:pathology; D005260:Female; D018628:Gene Dosage; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009373:Neoplasms, Germ Cell and Embryonal / Q000145:classification* / Q000235:genetics / Q000473:pathology; D018242:Neuroectodermal Tumors, Primitive / Q000145:classification* / Q000235:genetics / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D012189:Retrospective Studies; D059467:Transcriptome
keywords: brain; chromosomal aberrations; epigenetic; eye; medulloepithelioma