title: Somatic mutations of DICER1 and KMT2D are frequent in intraocular medulloepitheliomas.
abstract: Intraocular medulloepithelioma (IO-MEPL) is an uncommon embryonal neuroepithelial neoplasm of the eye. Little is known about the cytogenetics, molecular biology, and pathogenesis of this tumor. In the present study we investigated the mutational landscape of 19 IO-MEPL using targeted next-generation sequencing. Routinely prepared paraffin-embedded samples were assessed with high-coverage genome sequencing on the Illumina NextSeq 500 platform using a customized gene panel set covering the coding region of 130 genes. This revealed several notable genomic alterations, including mutations of DICER1 (6 tumors) and KMT2D (also known as MLL2; 5 tumors)-which are frequently recurrent and mutually exclusive molecular events for IO-MEPL. Non-recurrent mutations in the cancer-associated genes BRCA2, BRCA1, NOTCH2, CDH1, and GSE1 were also identified. IO-MEPL samples harboring a DICER1 mutation disclosed few chromosomal alterations and formed a separate DNA methylation cluster, indicating potential differences in genetic and epigenetic events arising perhaps from the presence of this aberration in the tumor genome. The high proportion of recurrent somatic DICER1 and KMT2D mutations in this series of sporadic IO-MEPL points to their likely important roles in the molecular pathogenesis of these rare embryonal tumors, and perhaps suggests the existence of distinct molecular variants of IO-MEPL. Although the precise role of these recurrent mutations in the development of IO-MEPL, and their relationship to pro-oncogenic molecular mechanisms, have yet to be determined, unraveling their roles could eventually be exploited for nonsurgical therapies of these neoplasms.
authors: Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), and Department of Neuropathology University Hospital, Heidelberg, Germany.|German Cancer Consortium (DKTK), Core Center, Heidelberg, Germany.
authors: Felix
authors: F
authors: Sahm
authors: David G. Cogan Ophthalmic Pathology Laboratory, Massachusetts Eye & Ear Infirmary, Harvard Medical School, Boston, MA.
authors: Frederick A
authors: FA
authors: Jakobiec
authors: Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), and Department of Neuropathology University Hospital, Heidelberg, Germany.|German Cancer Consortium (DKTK), Core Center, Heidelberg, Germany.
authors: Jochen
authors: J
authors: Meyer
authors: Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), and Department of Neuropathology University Hospital, Heidelberg, Germany.|German Cancer Consortium (DKTK), Core Center, Heidelberg, Germany.
authors: Daniel
authors: D
authors: Schrimpf
authors: John Hopkins University School of Medicine, Baltimore, MD.
authors: Charles G
authors: CG
authors: Eberhart
authors: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Volker
authors: V
authors: Hovestadt
authors: Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), and Department of Neuropathology University Hospital, Heidelberg, Germany.|German Cancer Consortium (DKTK), Core Center, Heidelberg, Germany.
authors: David
authors: D
authors: Capper
authors: German Cancer Consortium (DKTK), Core Center, Heidelberg, Germany.|Division of Pediatric Neuro-Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Sander
authors: S
authors: Lambo
authors: Department of Neuropathology, NN Burdenko Neurosurgical Institute, Moscow, Russia.
authors: Marina
authors: M
authors: Ryzhova
authors: Center of Neuropathology, Ludwig-Maximilians University, Munich, Germany.
authors: Ulrich
authors: U
authors: Schüller
authors: Department of Neuro-Oncology, Russian Scientific Center of Radiology, Moscow, Russia.
authors: Olga
authors: O
authors: Zheludkova
authors: Department of Neuro-Oncology, Federal Research Clinical Center for Pediatric Hematology, Oncology, Immunology, Moscow, Russia.
authors: Ella
authors: E
authors: Kumirova
authors: German Cancer Consortium (DKTK), Core Center, Heidelberg, Germany.|Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Peter
authors: P
authors: Lichter
authors: Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), and Department of Neuropathology University Hospital, Heidelberg, Germany.|German Cancer Consortium (DKTK), Core Center, Heidelberg, Germany.
authors: Andreas
authors: A
authors: von Deimling
authors: German Cancer Consortium (DKTK), Core Center, Heidelberg, Germany.|Division of Pediatric Neuro-Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: David T W
authors: DT
authors: Jones
authors: German Cancer Consortium (DKTK), Core Center, 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: Stefan M
authors: SM
authors: Pfister
authors: German Cancer Consortium (DKTK), Core Center, Heidelberg, Germany.|Division of Pediatric Neuro-Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Marcel
authors: M
authors: Kool
authors: Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), and Department of Neuropathology University Hospital, Heidelberg, Germany.|German Cancer Consortium (DKTK), Core Center, Heidelberg, Germany.
authors: Andrey
authors: A
authors: Korshunov
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005134:Eye Neoplasms / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D018242:Neuroectodermal Tumors, Primitive / Q000235:genetics*; D043244:Ribonuclease III / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C120898:KMT2D protein, human; D009363:Neoplasm Proteins; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases