Super-enhancer hypermutation alters oncogene expression in B cell lymphoma

Bal, Élodie; Kumar, Rahul; Hadigol, Mohammad; Holmes, Antony B.; Hilton, Laura K.; Loh, Jui Wan; Dreval, Kostiantyn; Wong, Jasper; Vlasevska, Sofija; Corinaldesi, Clarissa; Soni, Rajesh Kumar; Basso, Katia; Morin, Ryan D.; Khiabanian, Hossein; Pasqualucci, Laura; Dalla‐Favera, Riccardo

doi:10.1038/s41586-022-04906-8

Cited by 73 publications

(73 citation statements)

References 84 publications

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“…1c, see insert) 24,27 . We detected TFA-BT NCVs in multiple other genes with reported driver NCVs in promoters, including the highly mutated PLEKHS1, CDC20, DPH3, and BCL6 19,21,23,31,32 (Supplementary Fig. 1b).…”

Section: Prediction Of Cancer Driver Ncvsmentioning

confidence: 77%

“…A more recent analysis of 3,949 tumors from PCAWG and the Hartwig Medical Foundation identified driver NCVs in the promoters and enhancers of 52 genes 19 . Additional driver NCVs have been identified in the super-enhancers of BLC6, BCL2, CXCR4 in diffuse large B-cell lymphomas 23 . Whether this somewhat limited number of driver NCVs is due to a modest contribution of NCVs to cancer or to limitations of current approaches to identify and validate NCV drivers remains to be determined.…”

Section: Introductionmentioning

confidence: 99%

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Widespread perturbation of ETS factor binding sites in cancer

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Bray

et al. 2022

Preprint

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Although >90% of somatic mutations reside in non-coding regions, few have been reported as cancer drivers. To predict driver non-coding variants (NCVs), we present a novel transcription factor (TF)-aware burden test (TFA-BT) based on a model of coherent TF function in promoters. We applied our TFA-BT to NCVs from the Pan-Cancer Analysis of Whole Genomes cohort and predicted 2,555 driver NCVs in the promoters of 813 genes across 20 cancer-types. These genes are enriched in cancer-related gene ontologies, essential genes, and genes associated with cancer prognosis. We found that 765 candidate driver NCVs alter transcriptional activity, 510 lead to differential binding of TF-cofactor regulatory complexes, and that they primarily impact the binding of ETS factors. Finally, we show that different NCVs within a promoter often affect transcriptional activity through shared mechanisms. Our integrated computational and experimental approach shows that cancer NCVs are widespread and that ETS factors are commonly disrupted.

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Section: Prediction Of Cancer Driver Ncvsmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Widespread perturbation of ETS factor binding sites in cancer

Pro

Hook

Bray

et al. 2022

Preprint

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“…Recently, an advanced study resolved the pattern of hypermutations both at the whole-genome and regional scales and uncovered key mechanistic principles of carcinogenesis in diffuse large B cell lymphoma (DLBCL), a major non-Hodgkin blood cancer [ 3 ]. A cis-acting elements ranking employed by the application of the ROSE algorithm [ 81 ] on H3K27ac-ChIP-seq datasets coupled to computational assessments of the mutation frequency revealed that genomic loci harboring sequences with active SE characteristics encompass significantly higher levels of somatic mutations’ loads compared to other regions, e.g., randomly selected genomic loci, etc.…”

Section: Structural and Sequence Variations Of Enhancers And Super-en...mentioning

confidence: 99%

“…The establishment of tumor-oriented aberrant transcriptional states involves the reprogramming of the cellular epigenome, through the means of the structural and functional diversification of its cis-acting elements. It is well-addressed that cancer-associated sequence and chromatin architecture alterations are frequently localized within enhancers’ and SEs modules and can have a profound positive impact on tumor-oriented gene expression programs’ establishment [ 2 , 3 ]. Deregulation of transcription factors’ (TFs) function characterizes the pathogenesis of human cancers [ 4 ], and consequently the evolution of oncogenic transcription.…”

Section: Introductionmentioning

confidence: 99%

“…Such non-coding genomic abnormalities can generate direct or indirect, local or distant aberrant transcriptional regulatory output, which in turn integrates the mechanisms of gene transcription, facilitating the variation of the expression levels. Several TFs (e.g., MYC, MYCN, BCL6, p53) have been exhaustively studied and characterized as master regulators in distinct types of tumors [ 3 , 5 , 6 , 7 , 8 , 9 , 10 ], a fact that underscores the current understanding that describes cancer as a deleterious outcome of cellular gene expression dysregulation.…”

Section: Introductionmentioning

confidence: 99%

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Typical Enhancers, Super-Enhancers, and Cancers

Koutsi

Pouliou

Champezou

et al. 2022

Cancers

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Non-coding segments of the human genome are enriched in cis-regulatory modules that constitute functional elements, such as transcriptional enhancers and Super-enhancers. A hallmark of cancer pathogenesis is the dramatic dysregulation of the “archetype” gene expression profiles of normal human cells. Genomic variations can promote such deficiencies when occurring across enhancers and Super-enhancers, since they affect their mechanistic principles, their functional capacity and specificity, and the epigenomic features of the chromatin microenvironment across which these regulatory elements reside. Here, we comprehensively describe: fundamental mechanisms of gene expression dysregulation in cancers that involve genomic abnormalities within enhancers’ and Super-enhancers’ (SEs) sequences, which alter the expression of oncogenic transcription factors (TFs); cutting-edge technologies applied for the analysis of variation-enriched hotspots of the cancer genome; and pharmacological approaches for the treatment of Super-enhancers’ aberrant function. Finally, we provide an intratumor meta-analysis, which highlights that genomic variations in transcription-factor-driven tumors are accompanied overexpression of genes, a portion of which encodes for additional cancer-related transcription factors.

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The germinal center in the pathogenesis of B cell lymphomas

Pasqualucci

2023

Hematological Oncology

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The adaptive immune system has evolved to allow effective responses against a virtually unlimited number of invading pathogens. This process requires the transient formation of germinal centers (GC), a dynamic environment that ensures the generation and selection of B cells capable to produce antibodies with high antigen affinity, or to maintain the memory of that antigen for life. However, this comes at a cost, as the unique events accompanying the GC reaction pose a significant risk to the genome of B cells, which must endure elevated levels of replication stress, while proliferating at high rates and undergoing DNA breaks introduced by somatic hypermutation and class switch recombination. Indeed, the genetic/epigenetic disruption of programs implicated in normal GC biology has emerged as a hallmark of most B cell lymphomas. This improved understanding provides a conceptual framework for the identification of cellular pathways that could be exploited for precision medicine approaches.

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Super-enhancer hypermutation alters oncogene expression in B cell lymphoma

Cited by 73 publications

References 84 publications

Widespread perturbation of ETS factor binding sites in cancer

Widespread perturbation of ETS factor binding sites in cancer

Typical Enhancers, Super-Enhancers, and Cancers

The germinal center in the pathogenesis of B cell lymphomas

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