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  • 1
    Keywords: CANCER ; GENES ; PROTEINS ; SOMATIC MUTATIONS
    Abstract: Recent sequencing efforts have described the mutational landscape of the pediatric brain tumor medulloblastoma. Although MLL2 is among the most frequent somatic single nucleotide variants (SNV), the clinical and biological significance of these mutations remains uncharacterized. Through targeted re-sequencing, we identified mutations of MLL2 in 8 % (14/175) of MBs, the majority of which were loss of function. Notably, we also report mutations affecting the MLL2-binding partner KDM6A, in 4 % (7/175) of tumors. While MLL2 mutations were independent of age, gender, histological subtype, M-stage or molecular subgroup, KDM6A mutations were most commonly identified in Group 4 MBs, and were mutually exclusive with MLL2 mutations. Immunohistochemical staining for H3K4me3 and H3K27me3, the chromatin effectors of MLL2 and KDM6A activity, respectively, demonstrated alterations of the histone code in 24 % (53/220) of MBs across all subgroups. Correlating these MLL2- and KDM6A-driven histone marks with prognosis, we identified populations of MB with improved (K4+/K27-) and dismal (K4-/K27-) outcomes, observed primarily within Group 3 and 4 MBs. Group 3 and 4 MBs demonstrate somatic copy number aberrations, and transcriptional profiles that converge on modifiers of H3K27-methylation (EZH2, KDM6A, KDM6B), leading to silencing of PRC2-target genes. As PRC2-mediated aberrant methylation of H3K27 has recently been targeted for therapy in other diseases, it represents an actionable target for a substantial percentage of medulloblastoma patients with aggressive forms of the disease.
    Type of Publication: Journal article published
    PubMed ID: 23184418
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  • 2
    Publication Date: 2011-07-29
    Description: Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are the two most common non-Hodgkin lymphomas (NHLs). Here we sequenced tumour and matched normal DNA from 13 DLBCL cases and one FL case to identify genes with mutations in B-cell NHL. We analysed RNA-seq data from these and another 113 NHLs to identify genes with candidate mutations, and then re-sequenced tumour and matched normal DNA from these cases to confirm 109 genes with multiple somatic mutations. Genes with roles in histone modification were frequent targets of somatic mutation. For example, 32% of DLBCL and 89% of FL cases had somatic mutations in MLL2, which encodes a histone methyltransferase, and 11.4% and 13.4% of DLBCL and FL cases, respectively, had mutations in MEF2B, a calcium-regulated gene that cooperates with CREBBP and EP300 in acetylating histones. Our analysis suggests a previously unappreciated disruption of chromatin biology in lymphomagenesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3210554/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3210554/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Morin, Ryan D -- Mendez-Lago, Maria -- Mungall, Andrew J -- Goya, Rodrigo -- Mungall, Karen L -- Corbett, Richard D -- Johnson, Nathalie A -- Severson, Tesa M -- Chiu, Readman -- Field, Matthew -- Jackman, Shaun -- Krzywinski, Martin -- Scott, David W -- Trinh, Diane L -- Tamura-Wells, Jessica -- Li, Sa -- Firme, Marlo R -- Rogic, Sanja -- Griffith, Malachi -- Chan, Susanna -- Yakovenko, Oleksandr -- Meyer, Irmtraud M -- Zhao, Eric Y -- Smailus, Duane -- Moksa, Michelle -- Chittaranjan, Suganthi -- Rimsza, Lisa -- Brooks-Wilson, Angela -- Spinelli, John J -- Ben-Neriah, Susana -- Meissner, Barbara -- Woolcock, Bruce -- Boyle, Merrill -- McDonald, Helen -- Tam, Angela -- Zhao, Yongjun -- Delaney, Allen -- Zeng, Thomas -- Tse, Kane -- Butterfield, Yaron -- Birol, Inanc -- Holt, Rob -- Schein, Jacqueline -- Horsman, Douglas E -- Moore, Richard -- Jones, Steven J M -- Connors, Joseph M -- Hirst, Martin -- Gascoyne, Randy D -- Marra, Marco A -- 1U01CA114778/CA/NCI NIH HHS/ -- HHSN261200800001E/PHS HHS/ -- P50CA130805-01/CA/NCI NIH HHS/ -- TGT-53912/Canadian Institutes of Health Research/Canada -- U24 CA143866/CA/NCI NIH HHS/ -- U24 CA143866-01/CA/NCI NIH HHS/ -- U24 CA143866-02/CA/NCI NIH HHS/ -- U24 CA143866-03/CA/NCI NIH HHS/ -- England -- Nature. 2011 Jul 27;476(7360):298-303. doi: 10.1038/nature10351.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21796119" target="_blank"〉PubMed〈/a〉
    Keywords: Chromatin/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Genome, Human/genetics ; Histone Acetyltransferases/genetics/metabolism ; Histone-Lysine N-Methyltransferase/genetics/metabolism ; Histones/*metabolism ; Humans ; Loss of Heterozygosity/genetics ; Lymphoma, Follicular/enzymology/genetics ; Lymphoma, Large B-Cell, Diffuse/enzymology/genetics ; Lymphoma, Non-Hodgkin/enzymology/*genetics ; MADS Domain Proteins/genetics/metabolism ; MEF2 Transcription Factors ; Mutation/*genetics ; Myogenic Regulatory Factors/genetics/metabolism ; Neoplasm Proteins/genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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