Integrative whole-genome sequence analysis reveals roles of regulatory mutations in BCL6 and BCL2 in follicular lymphoma

Batmanov, Kirill; Wang, Wei; Bjørås, Magnar; Delabie, Jan; Wang, Junbai

doi:10.1038/s41598-017-07226-4

Cited by 17 publications

(46 citation statements)

References 76 publications

(97 reference statements)

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“…Finally, RPL39L 45 is involved in cancer stem cell self-renewal and hypoxia response. These results are concordant with other reports of non-coding regulatory mutations driving gene expression changes in B-cell lymphomas [46][47][48] .…”

Section: Discussionsupporting

confidence: 93%

Novel Mutation Hotspots within Non-Coding Regulatory Regions of the Chronic Lymphocytic Leukemia Genome

Orgueira

Antelo

Arias

et al. 2020

Sci Rep

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Mutations in non-coding DNA regions are increasingly recognized as cancer drivers. These mutations can modify gene expression in cis or by inducing high-order chormatin structure modifications with long-range effects. Previous analysis reported the detection of recurrent and functional noncoding DNA mutations in the chronic lymphocytic leukemia (CLL) genome, such as those in the 3′ untranslated region of NOTCH1 and in the PAX5 super-enhancer. In this report, we used whole genome sequencing data produced by the International Cancer Genome Consortium in order to analyze regions with previously reported regulatory activity. This approach enabled the identification of numerous recurrently mutated regions that were frequently positioned in the proximity of genes involved in immune and oncogenic pathways. By correlating these mutations with expression of their nearest genes, we detected significant transcriptional changes in genes such as PHF2 and S1PR2. More research is needed to clarify the function of these mutations in CLL, particularly those found in intergenic regions. A major part of mutations in the cancer genome occur in non-coding DNA regions, and their function is still beginning to be understood 1. Non-coding DNA comprises approximately 98% of the human genome, but recent research has proven that most of these regions are either part of regulatory motifs or actively transcribed to RNA 2,3. These mutations can induce functional genomic changes by altering the binding of transcription factors or by inducing high-order chromatin structural modifications 2,4. For example, mutations in 5′ and 3′ untranslated regions (UTRs) may disturb RNA structural conformation, modify microRNA binding sites or disrupt polyadenylation signals 2. In a similar fashion, mutations affecting non-protein coding genes such as microRNA and long intergenic RNA genes (lincRNAs) are known cancer driver events 2,5. Different studies have evidenced that the expression of genes such as BRCA1, CDH10, CCND1, MALAT1, PAX5, RB1, SDHD, TERT, TOX3, and TAL1 is influenced by non-coding DNA mutations in regulatory regions of the cancer genome 1,6,7. The Pancancer Analysis of Whole Genomes (PCAWG) project has revealed the existence of common and tumor-specific recurrently mutated functional elements near known cancer drivers 7. Some of these driver mutations can induce long-range changes in genome organization and trigger abnormal expression of distant oncogenes and tumor suppressors 8. Furthermore, the sequence distribution of these driver mutations is not random. Hornshøj et al. (2018) identified a significant enrichment in conserved CCCT-binding factor (CTCF) binding sites among recurrently mutated non-coding DNA regions with cancer specificity 6. Similarly, Line et al. (2019) identified 21 recurrently altered CTCF-rich insulator regions in the cancer genome, and elegantly demonstrated that some of these mutations drive tumor proliferation 9. Chronic Lymphocytic Leukemia (CLL) is among the most frequent lymphoproliferative disorders, and it is cha...

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Section: Discussionsupporting

confidence: 93%

Novel Mutation Hotspots within Non-Coding Regulatory Regions of the Chronic Lymphocytic Leukemia Genome

Orgueira

Antelo

Arias

et al. 2020

Sci Rep

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“…For example, many recurrent mutated regions in cancer genomes have been found to overlap with CTCF binding sites, showing a possible selection for these mutations ( Katainen et al, 2015 ; Lochovsky et al, 2015 ; Piraino and Furney, 2017 ). In addition, disruption of FOX TF binding sites in the BCL6 promoter have been reported in follicular lymphoma using an integrative approach that identifies functional regulatory mutation blocks ( Batmanov et al, 2017 ). Interestingly, both the creation and disruption of binding sites for the same TFs have been linked to cancer.…”

Section: Prediction Of Non-coding Snvs With High Functional Impactmentioning

confidence: 99%

Identification of Single Nucleotide Non-coding Driver Mutations in Cancer

et al. 2018

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Recent whole-genome sequencing studies have identified millions of somatic variants present in tumor samples. Most of these variants reside in non-coding regions of the genome potentially affecting transcriptional and post-transcriptional gene regulation. Although a few hallmark examples of driver mutations in non-coding regions have been reported, the functional role of the vast majority of somatic non-coding variants remains to be determined. This is because the few driver variants in each sample must be distinguished from the thousands of passenger variants and because the logic of regulatory element function has not yet been fully elucidated. Thus, variants prioritized based on mutational burden and location within regulatory elements need to be validated experimentally. This is generally achieved by combining assays that measure physical binding, such as chromatin immunoprecipitation, with those that determine regulatory activity, such as luciferase reporter assays. Here, we present an overview of in silico approaches used to prioritize somatic non-coding variants and the experimental methods used for functional validation and characterization.

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“…Batmanov et al [ 4 ] performed whole-genome sequencing in follicular lymphoma (FL) and found three novel highly recurrent regulatory mutation blocks near BCL6 and BCL2, genes known to be important in FL development. They also found the transcription factors whose binding may be disturbed by these mutations: disruption of the FOX-family near the BCL6 promoter results in reduced BCL6 expression.…”

Section: Biology Of Lymphomamentioning

confidence: 99%

New developments in the pathology of malignant lymphoma: a review of the literature published from May to August 2017

Krieken

2017

J Hematopathol

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Integrative whole-genome sequence analysis reveals roles of regulatory mutations in BCL6 and BCL2 in follicular lymphoma

Cited by 17 publications

References 76 publications

Novel Mutation Hotspots within Non-Coding Regulatory Regions of the Chronic Lymphocytic Leukemia Genome

Novel Mutation Hotspots within Non-Coding Regulatory Regions of the Chronic Lymphocytic Leukemia Genome

Identification of Single Nucleotide Non-coding Driver Mutations in Cancer

New developments in the pathology of malignant lymphoma: a review of the literature published from May to August 2017

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