Somatic mutations of DICER1 and KMT2D are frequent in intraocular medulloepitheliomas
Felix Sahm
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
Search for more papers by this authorFrederick A. Jakobiec
David G. Cogan Ophthalmic Pathology Laboratory, Massachusetts Eye & Ear Infirmary, Harvard Medical School, Boston, MA
Search for more papers by this authorJochen Meyer
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
Search for more papers by this authorDaniel Schrimpf
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
Search for more papers by this authorCharles G. Eberhart
John Hopkins University School of Medicine, Baltimore, MD
Search for more papers by this authorVolker Hovestadt
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
Search for more papers by this authorDavid Capper
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
Search for more papers by this authorSander Lambo
German Cancer Consortium (DKTK), Core Center, Heidelberg, Germany
Division of Pediatric Neuro-Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
Search for more papers by this authorMarina Ryzhova
Department of Neuropathology, NN Burdenko Neurosurgical Institute, Moscow, Russia
Search for more papers by this authorUlrich Schüller
Center of Neuropathology, Ludwig-Maximilians University, Munich, Germany
Search for more papers by this authorOlga Zheludkova
Department of Neuro-Oncology, Russian Scientific Center of Radiology, Moscow, Russia
Search for more papers by this authorElla Kumirova
Department of Neuro-Oncology, Federal Research Clinical Center for Pediatric Hematology, Oncology, Immunology, Moscow, Russia
Search for more papers by this authorPeter Lichter
German Cancer Consortium (DKTK), Core Center, Heidelberg, Germany
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
Search for more papers by this authorAndreas von Deimling
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
Search for more papers by this authorDavid T. W. Jones
German Cancer Consortium (DKTK), Core Center, Heidelberg, Germany
Division of Pediatric Neuro-Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
Search for more papers by this authorStefan M. Pfister
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
Search for more papers by this authorMarcel Kool
German Cancer Consortium (DKTK), Core Center, Heidelberg, Germany
Division of Pediatric Neuro-Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
Search for more papers by this authorCorresponding Author
Andrey Korshunov
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
Correspondence to: Andrey Korshunov, German Cancer Research Center (DKFZ), Im Neuenheimer Feld, 280, 69120 Heidelberg, Germany. E-mail: [email protected]Search for more papers by this authorFelix Sahm
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
Search for more papers by this authorFrederick A. Jakobiec
David G. Cogan Ophthalmic Pathology Laboratory, Massachusetts Eye & Ear Infirmary, Harvard Medical School, Boston, MA
Search for more papers by this authorJochen Meyer
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
Search for more papers by this authorDaniel Schrimpf
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
Search for more papers by this authorCharles G. Eberhart
John Hopkins University School of Medicine, Baltimore, MD
Search for more papers by this authorVolker Hovestadt
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
Search for more papers by this authorDavid Capper
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
Search for more papers by this authorSander Lambo
German Cancer Consortium (DKTK), Core Center, Heidelberg, Germany
Division of Pediatric Neuro-Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
Search for more papers by this authorMarina Ryzhova
Department of Neuropathology, NN Burdenko Neurosurgical Institute, Moscow, Russia
Search for more papers by this authorUlrich Schüller
Center of Neuropathology, Ludwig-Maximilians University, Munich, Germany
Search for more papers by this authorOlga Zheludkova
Department of Neuro-Oncology, Russian Scientific Center of Radiology, Moscow, Russia
Search for more papers by this authorElla Kumirova
Department of Neuro-Oncology, Federal Research Clinical Center for Pediatric Hematology, Oncology, Immunology, Moscow, Russia
Search for more papers by this authorPeter Lichter
German Cancer Consortium (DKTK), Core Center, Heidelberg, Germany
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
Search for more papers by this authorAndreas von Deimling
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
Search for more papers by this authorDavid T. W. Jones
German Cancer Consortium (DKTK), Core Center, Heidelberg, Germany
Division of Pediatric Neuro-Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
Search for more papers by this authorStefan M. Pfister
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
Search for more papers by this authorMarcel Kool
German Cancer Consortium (DKTK), Core Center, Heidelberg, Germany
Division of Pediatric Neuro-Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
Search for more papers by this authorCorresponding Author
Andrey Korshunov
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
Correspondence to: Andrey Korshunov, German Cancer Research Center (DKFZ), Im Neuenheimer Feld, 280, 69120 Heidelberg, Germany. E-mail: [email protected]Search for more papers by this authorSupported by: the German Cancer Research Center (DKFZ)—Heidelberg Center for Personalized Oncology (HIPO) Personalized Oncology Programm (POP).
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. © 2016 Wiley Periodicals, Inc.
Supporting Information
Additional Supporting Information may be found in the online version of this article.
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| gcc22344-sup-0003-suppinfotab03.docx14.1 KB | Supporting Information Table 3. |
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