Recurrent mutation of the ID3 gene in Burkitt lymphoma identified by integrated genome, exome and transcriptome sequencing

Richter, Julia; Schlesner, Matthias; Hoffmann, Steve; Kreuz, Markus; Leich, Ellen; Burkhardt, Birgit; Rosołowski, Maciej; Ammerpohl, Ole; Wagener, Rabea; Bernhart, Stephan H.; Lenze, Dido; Szczepanowski, Monika; Paulsen, Maren; Lipinski, Simone; Russell, Robert B.; Adam‐Klages, Sabine; Apic, Gordana; Claviez, Alexander; Hasenclever, Dirk; Hovestadt, Volker; Hornig, Nadine; Korbel, Jan O.; Kube, Dieter; Langenberger, David; Lawerenz, Chris; Lisfeld, Jasmin; Meyer, Katharina; Picelli, Simone; Pischimarov, Jordan; Radlwimmer, Bernhard; Rausch, Tobias; Rohde, Marius; Schilhabel, Markus B.; Scholtysik, René; Spang, Rainer; Trautmann, Heiko; Zenz, Thorsten; Borkhardt, Arndt; Drexler, Hans; Möller, Peter; MacLeod, Roderick A.F.; Pott, Christiane; Schreiber, Stefan; Trümper, Lorenz; Loeffler, Markus; Stadler, Peter F.; Lichter, Peter; Eils, Roland; Küppers, Ralf; Hummel, Michael; Klapper, Wolfram; Rosenstiel, Philip; Rosenwald, Andreas; Brors, Benedikt; Siebert, Reiner

doi:10.1038/ng.2469

Cited by 374 publications

(143 citation statements)

References 57 publications

(66 reference statements)

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“…We propose that many novel cancer candidates can be annotated to specific processes based on their interactions with Cancer Census gene products and known participation in cellular pathways. For example, the candidate protein ID3, a DNA-binding inhibitor, interacts with the two Cancer Census transcription factors TCF12 and TCF3, suggesting a role for ID3 in the regulation of transcription by inhibiting binding of specific transcription factors to DNA (Loveys et al, 1996; Richter et al, 2012). CTBP2, which we identified as a potential suppressor in lymphoid tumors, represents another example (Figure 5E and Figure S7).…”

Section: Resultsmentioning

confidence: 99%

A Proteome-Scale Map of the Human Interactome Network

Rolland

Taşan

Charloteaux

et al. 2014

Cell

1,244

1,225

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SUMMARY Just as reference genome sequences revolutionized human genetics, reference maps of interactome networks will be critical to fully understand genotype-phenotype relationships. Here, we describe a systematic map of ~14,000 high-quality human binary protein-protein interactions. At equal quality, this map is ~30% larger than what is available from small-scale studies published in the literature in the last few decades. While currently available information is highly biased and only covers a relatively small portion of the proteome, our systematic map appears strikingly more homogeneous, revealing a “broader” human interactome network than currently appreciated. The map also uncovers significant inter-connectivity between known and candidate cancer gene products, providing unbiased evidence for an expanded functional cancer landscape, while demonstrating how high quality interactome models will help “connect the dots” of the genomic revolution.

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Section: Resultsmentioning

confidence: 99%

A Proteome-Scale Map of the Human Interactome Network

Rolland

Taşan

Charloteaux

et al. 2014

Cell

1,244

1,225

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“…Whole-genome bisulphite library preparation was carried out as recently described 33 , with modifications to a previously published protocol 34 . In brief, 5µg of genomic DNA were sheared using a Covaris device (Covaris Inc.).…”

Section: High-throughput Sequencing Data Generationmentioning

confidence: 99%

Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma

Northcott

Lee

Zichner

et al. 2014

Nature

528

450

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Summary Paragraph Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation, and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoural heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and Group 4 subgroup medulloblastomas account for the majority of paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to Groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family protooncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1/GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate ‘enhancer hijacking’ as an efficient mechanism driving oncogene activation in a childhood cancer.

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“…A database survey revealed that TSC1 ‐mRNA expression is the highest in Burkitt's lymphoma‐derived cell lines compared to 36 different tumor‐type cell lines in the Cancer Cell Line Encyclopedia (CCLE; http://www.broadinstitute.org/ccle) (Fig EV1A). Moreover, the COSMIC database (http://cancer.sanger.ac.uk/cancergenome/projects/cosmic/) lists no mutations for TSC1 or TSC2 in Burkitt's lymphoma and they are not under the recurrently mutated genes in Burkitt's lymphoma identified by genomic approaches in two studies (Richter et al , 2012; Schmitz et al , 2012). Burkitt's lymphoma is an aggressively growing malignancy characterized by a MYC translocation that induces very high expression levels of the proto‐oncogenic transcription factor MYC (Molyneux et al , 2012).…”

Section: Introductionmentioning

confidence: 99%

Tuberous sclerosis complex is required for tumor maintenance in MYC‐driven Burkitt's lymphoma

et al. 2018

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The tuberous sclerosis complex (TSC) 1/2 is a negative regulator of the nutrient‐sensing kinase mechanistic target of rapamycin complex (mTORC1), and its function is generally associated with tumor suppression. Nevertheless, biallelic loss of function of TSC1 or TSC2 is rarely found in malignant tumors. Here, we show that TSC1/2 is highly expressed in Burkitt's lymphoma cell lines and patient samples of human Burkitt's lymphoma, a prototypical MYC‐driven cancer. Mechanistically, we show that MYC induces TSC1 expression by transcriptional activation of the TSC1 promoter and repression of miR‐15a. TSC1 knockdown results in elevated mTORC1‐dependent mitochondrial respiration enhanced ROS production and apoptosis. Moreover, TSC1 deficiency attenuates tumor growth in a xenograft mouse model. Our study reveals a novel role for TSC1 in securing homeostasis between MYC and mTORC1 that is required for cell survival and tumor maintenance in Burkitt's lymphoma. The study identifies TSC1/2 inhibition and/or mTORC1 hyperactivation as a novel therapeutic strategy for MYC‐driven cancers.

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Recurrent mutation of the ID3 gene in Burkitt lymphoma identified by integrated genome, exome and transcriptome sequencing

Cited by 374 publications

References 57 publications

A Proteome-Scale Map of the Human Interactome Network

A Proteome-Scale Map of the Human Interactome Network

Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma

Tuberous sclerosis complex is required for tumor maintenance in MYC‐driven Burkitt's lymphoma

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