Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin

Rd, Morin; Johnson, Nick R.; Tm, Severson; Mungall, Andrew J.; J, An; Goya, Rodrigo; Je, Paul; Boyle, M; Bw, Woolcock; Kuchenbauer, Florian; Yap, Damian; Humphries, R. Keith; Griffith, Obi L.; Shah, Sohrab P.; Zhu, Hai‐Liang; Kimbara, Michelle; Shashkin, Pavel; Jf, Charlot; Tcherpakov, Marianna; Corbett, Richard; A, Tam; Varhol, Richard; Smailus, Duane E.; Moksa, Michelle; Zhao, Yongjun; Delaney, Allen; Qian, Hong; Birol, İnanç; Schein, Jacquie; Moore, Richard A.; Holt, Robert A.; Horsman, DE; Jm, Connors; Jones, Steven J.M.; Aparicio, Samuel; Hirst, Martin; Rd, Gascoyne; Ma, Marra

doi:10.1038/ng.518

Cited by 1,512 publications

(1,246 citation statements)

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“…Transcriptome sequence data RNA-seq data included 31 DLBCL libraries (each RNA-seq library is constructed from a single tumor sample) described by Morin et al 18 and 58 additional DLBCL libraries. 19 Briefly, paired end reads, obtained by sequencing both ends of each DNA fragment of an RNA-seq library, were aligned to the human reference genome (hg18) and exon junction sequences (to allow correct alignment of reads spanning exons) using the Burrows-Wheeler Aligner.…”

Section: Cytogenetic Analysismentioning

confidence: 99%

“…16 Using the transcriptome sequencing method RNA-seq 17 in 89 DLBCL samples, we recently identified genomic changes that drive the pathogenesis of adult DLBCL. 18,19 The most commonly mutated gene, mutated in 33/89 transcriptomes (37%) was BCL2. 19 The aims of the current study were to determine the frequency and distribution of BCL2 mutations in DLBCL in a large number of cases, assess the relationship between gene mutation and BCL2 protein expression or BCL2 translocation, and determine the impact of mutations on immunohistochemical detection of protein expression and clinical outcome.…”

Section: Introductionmentioning

confidence: 99%

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BCL2 mutations in diffuse large B-cell lymphoma

et al. 2011

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BCL2 is deregulated in diffuse large B-cell lymphoma (DLBCL) by the t(14;18) translocation, gene amplification and/or nuclear factor-kB signaling. RNA-seq data have recently shown that BCL2 is the most highly mutated gene in germinal center B-cell (GCB) DLBCL. We have sequenced BCL2 in 298 primary DLBCL biopsies, 131 additional non-Hodgkin lymphoma biopsies, 24 DLBCL cell lines and 51 germline DNAs. We found frequent BCL2 mutations in follicular lymphoma (FL) and GCB DLBCL, but low levels of BCL2 mutations in activated B-cell DLBCL, mantle cell lymphoma, small lymphocytic leukemia and peripheral T-cell lymphoma. We found no BCL2 mutations in GC centroblasts. Many mutations were non-synonymous; they were preferentially located in the flexible loop domain, with few in BCL2-homology domains. An elevated transition/transversions ratio supports that the mutations result from somatic hypermutation. BCL2 translocations correlate with, and are likely important in acquisition of, additional BCL2 mutations in GCB DLBCL and FL. DLBCL mutations were not independently associated with survival. Although previous studies of BCL2 mutations in FL have reported mutations to result in pseudo-negative BCL2 protein expression, we find this rare in de-novo DLBCL.Leukemia ( BCL2, discovered because of its involvement in t(14;18) in follicular lymphoma (FL), 3 has a central role in the inhibition of apoptosis. 4 BCL2 is normally transiently expressed during B-cell maturation. The t(14;18) translocation causes constitutive overexpression of BCL2 by juxtaposing it to immunoglobulin heavy chain gene enhancer elements. This translocation is found in B20% of DLBCL, 5 most often in the GCB subtype of DLBCL. 6 Other mechanisms of BCL2 deregulation, more often observed in ABC DLBCLs, include amplification of the BCL2 gene or its transcriptional upregulation through constitutive activation of the nuclear factor-kB pathway. 7 Saito et al. 8 reported that the BCL2 promoter can also be aberrantly hypermutated in DLBCL, which may prevent its inhibition by MIZ1 and BCL6. 8 They found a high number of mutations in BCL2 and suggested that the mutations described were the result of somatic hypermutation (SHM). Mutations in BCL2 have been shown to cause false-negative protein expression results in immunohistochemistry assays in FL; 9,10 however, no large study has so far investigated whether this occurs in DLBCL.

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Section: Cytogenetic Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

BCL2 mutations in diffuse large B-cell lymphoma

et al. 2011

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“…Several studies have described overexpression of EZH2 in human cancers, including prostate and breast cancer, as well as in lymphoma (Varambally et al, 2002;Simon and Lange, 2008). Importantly, while cancer genome sequencing approaches detected inactivating EZH2 mutations in myeloid leukemias (Ernst et al, 2010;Nikoloski et al, 2010), they also uncovered specific heterozygous point mutations of EZH2 in lymphomas (Morin et al, 2010). These point mutations cause an enhanced capacity of EZH2 to di and trimethylate H3K27 (Sneeringer et al, 2010) and could thus drive the establishment of cancerspecific epigenetic programs.…”

Section: Epigenetic Side Effects Of Global Dna Demethylationmentioning

confidence: 99%

Epigenetic cancer therapy: rationales, targets and drugs

2011

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The fundamental role of altered epigenetic modification patterns in tumorigenesis establishes epigenetic regulatory enzymes as important targets for cancer therapy. Over the past few years, several drugs with an epigenetic activity have received approval for the treatment of cancer patients, which has led to a detailed characterization of their modes of action. The results showed that both established drug classes, the histone deacetylase (HDAC) inhibitors and the DNA methyltransferase inhibitors, show substantial limitations in their epigenetic specificity. HDAC inhibitors are highly specific drugs, but the enzymes have a broad substrate specificity and deacetylate numerous proteins that are not associated with epigenetic regulation. Similarly, the induction of global DNA demethylation by non-specific inhibition of DNA methyltransferases shows pleiotropic effects on epigenetic regulation with no apparent tumor-specificity. Second-generation azanucleoside drugs have integrated the knowledge about the cellular uptake and metabolization pathways, but do not show any increased specificity for cancer epigenotypes. As such, the traditional rationale of epigenetic cancer therapy appears to be in need of refinement, as we move from the global inhibition of epigenetic modifications toward the identification and targeting of tumor-specific epigenetic programs. Recent studies have identified epigenetic mechanisms that promote self-renewal and developmental plasticity in cancer cells. Druggable somatic mutations in the corresponding epigenetic regulators are beginning to be identified and should facilitate the development of epigenetic therapy approaches with improved tumor specificity.

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“…It has been long accepted that many types of B cell cancer (lymphomas, myelomas, plasmacytomas, etc) are derived from the antigen-stimulated B cell Germinal Center (GC) reaction [1][2][3][4] i.e. they are aberrant products of the somatic hypermutation mechanism normally targeting rearranged immunoglobulin (Ig) variable genes (so called V[D]J regions).…”

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confidence: 99%