TY  - JOUR
AU  - Sahm, Felix
AU  - Jakobiec, Frederick A
AU  - Meyer, Jochen
AU  - Schrimpf, Daniel
AU  - Eberhart, Charles G
AU  - Hovestadt, Volker
AU  - Capper, David
AU  - Lambo, Sander
AU  - Ryzhova, Marina
AU  - Schüller, Ulrich
AU  - Zheludkova, Olga
AU  - Kumirova, Ella
AU  - Lichter, Peter
AU  - von Deimling, Andreas
AU  - Jones, David
AU  - Pfister, Stefan
AU  - Kool, Marcel
AU  - Korshunov, Andrey
TI  - Somatic mutations of DICER1 and KMT2D are frequent in intraocular medulloepitheliomas.
JO  - Genes, chromosomes & cancer
VL  - 55
IS  - 5
SN  - 1045-2257
CY  - New York, NY
PB  - Wiley-Liss
M1  - DKFZ-2017-05544
SP  - 418 - 427
PY  - 2016
AB  - 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.
KW  - DNA-Binding Proteins (NLM Chemicals)
KW  - MLL2 protein, human (NLM Chemicals)
KW  - Neoplasm Proteins (NLM Chemicals)
KW  - DICER1 protein, human (NLM Chemicals)
KW  - Ribonuclease III (NLM Chemicals)
KW  - DEAD-box RNA Helicases (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:26841698
DO  - DOI:10.1002/gcc.22344
UR  - https://inrepo02.dkfz.de/record/130465
ER  -