The Genetic Landscape of Mutations in Burkitt Lymphoma
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ABSTRACT: Burkitt lymphoma (BL) is characterized by deregulation of MYC, but the contribution of other genetic mutations to the disease is largely unknown. We sequenced exomes of 59 BL tumors, 14 of which had paired normal tissue. Our work elucidates commonly occurring gene-coding mutations in Burkitt lymphoma and implicates ID3 as a novel tumor suppressor gene.
SECONDARY ACCESSION(S): PRJNA178385PRJNA178386
REPOSITORIES: dbGaP
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Project description:Burkitt lymphoma is characterized by deregulation of MYC, but the contribution of other genetic mutations to the disease is largely unknown. Here, we describe the first completely sequenced genome from a Burkitt lymphoma tumor and germline DNA from the same affected individual. We further sequenced the exomes of 59 Burkitt lymphoma tumors and compared them to sequenced exomes from 94 diffuse large B-cell lymphoma (DLBCL) tumors. We identified 70 genes that were recurrently mutated in Burkitt lymphomas, including ID3, GNA13, RET, PIK3R1 and the SWI/SNF genes ARID1A and SMARCA4. Our data implicate a number of genes in cancer for the first time, including CCT6B, SALL3, FTCD and PC. ID3 mutations occurred in 34% of Burkitt lymphomas and not in DLBCLs. We show experimentally that ID3 mutations promote cell cycle progression and proliferation. Our work thus elucidates commonly occurring gene-coding mutations in Burkitt lymphoma and implicates ID3 as a new tumor suppressor gene.
2013-07-01 | GSE48435 | GEO
Project description:Burkitt lymphoma is characterized by deregulation of MYC, but the contribution of other genetic mutations to the disease is largely unknown. Here, we describe the first completely sequenced genome from a Burkitt lymphoma tumor and germline DNA from the same affected individual. We further sequenced the exomes of 59 Burkitt lymphoma tumors and compared them to sequenced exomes from 94 diffuse large B-cell lymphoma (DLBCL) tumors. We identified 70 genes that were recurrently mutated in Burkitt lymphomas, including ID3, GNA13, RET, PIK3R1 and the SWI/SNF genes ARID1A and SMARCA4. Our data implicate a number of genes in cancer for the first time, including CCT6B, SALL3, FTCD and PC. ID3 mutations occurred in 34% of Burkitt lymphomas and not in DLBCLs. We show experimentally that ID3 mutations promote cell cycle progression and proliferation. Our work thus elucidates commonly occurring gene-coding mutations in Burkitt lymphoma and implicates ID3 as a new tumor suppressor gene. Gene expression profiling on 21 Burkitt lymphomas was performed using standard Affymetrix protocols as described previously. Briefly, 1 μg of total RNA was reverse transcribed, using oligo(dT) primer to synthesize cDNA. T7 primer was used for in vitro transcription, resulting in labeled cRNA, which was fragmented and hybridized to Affymetrix Whole-Genome Gene 1.0 ST microarrays. Microarrays were washed and scanned, and the data were normalized as described previously.
2013-07-01 | E-GEOD-48435 | biostudies-arrayexpress
Project description:<p>Burkitt lymphoma (BL) is characterized by deregulation of <i>MYC</i>, but the contribution of other genetic mutations to the disease is largely unknown. We sequenced exomes of 59 BL tumors, 14 of which had paired normal tissue. Our work elucidates commonly occurring gene-coding mutations in Burkitt lymphoma and implicates <i>ID3</i> as a novel tumor suppressor gene.</p>
| phs000562.v1.p1 | EGA
Project description:This SuperSeries is composed of the following subset Series: GSE33474: Tristetraprolin is a tumor suppressor that impairs Myc-induced lymphoma and abolishes the malignant state [bone marrow B cells]. GSE37790: Tristetraprolin is a tumor suppressor that impairs Myc-induced lymphoma and abolishes the malignant state [Lymphoma]. GSE37791: Tristetraprolin is a tumor suppressor that impairs Myc-induced lymphoma and abolishes the malignant state [retrovirally infected ex vivo lymphoma] Refer to individual Series
2012-08-01 | E-GEOD-37792 | biostudies-arrayexpress
Project description:Angioimmunoblastic T-Cell lymphoma (AITL) is a mature T-cell lymphoma of blood or lymph vessel immunoblasts. It is the most common subtype of T-cell lymphoma in the Western world and the second most frequent one in Asia. We sequenced nine pairs of AITL exomes and their matched normals. Frequent mutations in TET2 and RHOA were detected, and confirmed through targeted sequencing in a larger cohort of 43 samples. Gene expression profiling was performed to identify genes differentially expressed between patients with and without mutations in genes of interest.
2018-09-14 | GSE51521 | GEO
Project description:BCL6 is a key oncogene in lymphoma pathogenesis. The expression of BCL6 in lymphoid cells can be deregulated by several mechanisms, including chromosomal translocations, somatic mutations in the promoter regulatory regions or reduced proteasome-mediated degradation. FBXO11 was recently identified as a major ubiquitin ligase involved in the degradation of BCL6 and is frequently inactivated in diffuse large B-cell lymphoma (DLBCL). In this work, we found that FBXO11 is frequently mutated in Burkitt lymphoma (BL) but rarely mutated in other BCL6-positive lymphomas, such as follicular lymphoma (FL). All mutations tested impaired FBXO11 mediated BCL6 degradation and FBXO11 knock-out completely stabilized BCL6 levels in human BL cell lines. Conditional deletion of one copy or both copies of FBXO11 in c-Myc-driven B cell lymphoma in mice accelerated lymphomagenesis, genetically confirming that FBXO11 is a haplo-insufficient oncosuppressor in lymphoma. In both FBOX11 WT and deficient BL mouse and human cell lines, blockade of BCL6 via a specific degrader or BCL6 inhibitors, impaired lymphoma growth in vitro and in vivo, an effect further enhanced by co-inhibition of c-Myc activity. Overall these findings not only establish FBXO11 as one of the most frequently mutated genes in BL, but also elucidate its biological functions in lymphomagenesis and thereby identify BCL6 as a specific therapeutic target in BL.
2021-12-31 | GSE159303 | GEO
Project description:The ABC subtype of diffuse large B cell lymphoma (DLBCL) remains the least curable form of this lymphoma despite recent advances in therapy. We have combined structural and functional genomics to triangulate on new oncogenic mechanisms and devise new therapeutic strategies. RNA interference screen revealed a dependence of ABC DLBCL cell lines on MYD88 and IRAK1. High throughput resequencing of RNA (RNA-Seq) revealed frequent somatic mutations in MYD88 that preferentially occurred in the ABC DLBCL subtype. Remarkably, one third of ABC DLBCL tumor samples harbored the same amino acid substitution, L265P, in the MYD88 TIR domain at an evolutionarily invariant residue in its hydrophobic core. This mutation was rare or absent in two other DLBCL subtypes, but was observed in 9% of MALT lymphomas. At a lower frequency, multiple other mutations were observed in the MYD88 TIR domain, occurring in both the ABC and GCB subtypes of DLBCL. Survival of ABC DLBCL lines bearing the L265P mutation was sustained by the mutant but not wild type MYD88 isoform, demonstrating that this MYD88 mutant is oncogenic and gain-of-function. The MYD88 L265P mutant assembled a protein complex that spontaneous triggers the phosphorylation of IRAK1, leading to NF-kB signaling, secretion of the cytokines IL-6, IL-10 and interferon-b, and JAK kinase signaling. These findings demonstrate that the MYD88 signaling pathway is integral to the pathogenesis of ABC DLBCL, providing a genetic rationale for therapeutic targeting of the MYD88 signaling pathway in this lymphoma subtype.
2010-12-30 | GSE22900 | GEO
Project description:Normal-cell counterparts of solid and myeloid tumors accumulate mutations years before disease onset; whether this occurs in B-lymphocytes prior to lymphoma remains uncertain. We sequenced multiple stages of the B-lineage in elderly individuals and patients with lymphoplasmacytic lymphoma, a singular disease for studying lymphomagenesis because of high-prevalence of mutated MYD88. We observed similar accumulation of random mutations in B-lineages from both cohorts and, unexpectedly, found MYD88L265P in normal precursor and mature B-lymphocytes from lymphoma patients. We uncovered genetic and transcriptional pathways driving malignant transformation and leveraged these to model lymphoplasmacytic lymphoma in mice, based on mutated MYD88 in B-cell precursors and BCL2 overexpression. Thus, MYD88L265P is a pre-neoplastic event, which challenges current understanding of lymphomagenesis and may have implications for early detection of B-cell lymphomas.
2021-11-04 | GSE185156 | GEO
Project description:Normal-cell counterparts of solid and myeloid tumors accumulate mutations years before disease onset; whether this occurs in B-lymphocytes prior to lymphoma remains uncertain. We sequenced multiple stages of the B-lineage in elderly individuals and patients with lymphoplasmacytic lymphoma, a singular disease for studying lymphomagenesis because of high-prevalence of mutated MYD88. We observed similar accumulation of random mutations in B-lineages from both cohorts and, unexpectedly, found MYD88L265P in normal precursor and mature B-lymphocytes from lymphoma patients. We uncovered genetic and transcriptional pathways driving malignant transformation and leveraged these to model lymphoplasmacytic lymphoma in mice, based on mutated MYD88 in B-cell precursors and BCL2 overexpression. Thus, MYD88L265P is a pre-neoplastic event, which challenges current understanding of lymphomagenesis and may have implications for early detection of B-cell lymphomas.
2021-11-04 | GSE185157 | GEO
Project description:Mutations in genes encoding the various subunits of the SWI/SNF chromatin remodeling complex are frequently observed in different human cancers. In diffuse large B-cell lymphoma (DLBCL), genetic changes in BCL7A, a subunit of the SWI/SNF complex, have been recently reported but the functional role of such genetic changes remains unknown. BCL7A mutations concentrate at the first exon and the most frequently mutated hotspot is the splice donor site of the first intron. By using in vitro and in vivo analyses, we show that restoration of BCL7A drives a tumor suppressor-like phenotype. Further, we found that splice site mutations block the tumor suppressor phenotype and prevent BCL7A from binding to the SWI/SNF complex. Finally, we identified that the SWI/SNF complex accumulates mutations in a third of DLBCL tumors, especially in the GCB subtype. These discoveries highlight the tumor suppressor role of BCL7A mutations in DLBCL, and suggest that the SWI/SNF complex is involved in DLBCL pathogenesis.
2020-10-21 | PXD014795 | Pride