Somatic mutations of DICER1 and KMT2D are frequent in intraocular medulloepitheliomas

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• 作者：Felix Sahm ; Frederick A. Jakobiec ; Jochen Meyer ; Daniel Schrimpf ; Charles G. Eberhart ; Volker Hovestadt ; David Capper ; Sander Lambo ; Marina Ryzhova ; Ulrich Sch&#252 ; ller ; Olga Zheludkova ; Ella Kumirova ; Peter Lichter ; Andreas von Deimling ; David T. W. Jones ; Stefan M. Pfister ; Marcel Kool and Andrey Korshunov
• 刊名：Genes, Chromosomes and Cancer
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：55
• 期：5
• 页码：418-427
• 全文大小：713K
• ISSN：1098-2264

文摘

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 m>DICER1m> (6 tumors) and m>KMT2Dm> (also known as m>MLL2m>; 5 tumors)—which are frequently recurrent and mutually exclusive molecular events for IO-MEPL. Non-recurrent mutations in the cancer-associated genes m>BRCA2, BRCA1, NOTCH2, CDH1m>, and m>GSE1m> were also identified. IO-MEPL samples harboring a m>DICER1m> 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 m>DICER1m> and m>KMT2Dm> 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.