The Genetic Landscape of Mutations in Burkitt Lymphoma
Ontology highlight
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.
PROVIDER: phs000562.v1.p1 | EGA |
REPOSITORIES: EGA
Publications
The genetic landscape of mutations in Burkitt lymphoma.
Love Cassandra C Sun Zhen Z Jima Dereje D Li Guojie G Zhang Jenny J Miles Rodney R Richards Kristy L KL Dunphy Cherie H CH Choi William W L WW Srivastava Gopesh G Lugar Patricia L PL Rizzieri David A DA Lagoo Anand S AS Bernal-Mizrachi Leon L Mann Karen P KP Flowers Christopher R CR Naresh Kikkeri N KN Evens Andrew M AM Chadburn Amy A Gordon Leo I LI Czader Magdalena B MB Gill Javed I JI Hsi Eric D ED Greenough Adrienne A Moffitt Andrea B AB McKinney Matthew M Banerjee Anjishnu A Grubor Vladimir V Levy Shawn S Dunson David B DB Dave Sandeep S SS
Nature genetics 20121111 12
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 lym ...[more]
Similar Datasets
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 | dbGaP
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:Burkitt lymphoma (BL) can often be cured by intensive chemotherapy, but the toxicity of such therapy precludes its use in the elderly and in patients with endemic BL (eBL) in developing countries, necessitating new strategies. The normal germinal center B cell is the presumed cell of origin for both BL and diffuse large B cell lymphoma (DLBCL), yet gene expression analysis suggests that these malignancies may utilize different oncogenic pathways. BL is subdivided into a sporadic subtype (sBL) that is diagnosed in developed countries, the EBV-associated eBL subtype, and an HIV-associated subtype (hivBL), but it is unclear whether these subtypes employ similar or divergent oncogenic mechanisms. Here we used high throughput RNA sequencing and RNA interference screening to discover essential regulatory pathways that cooperate with MYC, the defining oncogene of this cancer. In 70% of sBL cases, mutations affecting the transcription factor TCF3 (E2A) or its negative regulator ID3 fostered TCF3 dependency. TCF3 activated the pro-survival PI(3) kinase pathway in BL, in part by augmenting tonic B cell receptor signaling. In 38% of sBL cases, oncogenic CCND3 mutations produced highly stable cyclin D3 isoforms that drive cell cycle progression. These findings suggest opportunities to improve therapy for patients with BL.
2012-08-16 | GSE35163 | GEO
Project description:Burkitt lymphoma (BL) can often be cured by intensive chemotherapy, but the toxicity of such therapy precludes its use in the elderly and in patients with endemic BL (eBL) in developing countries, necessitating new strategies. The normal germinal center B cell is the presumed cell of origin for both BL and diffuse large B cell lymphoma (DLBCL), yet gene expression analysis suggests that these malignancies may utilize different oncogenic pathways. BL is subdivided into a sporadic subtype (sBL) that is diagnosed in developed countries, the EBV-associated eBL subtype, and an HIV-associated subtype (hivBL), but it is unclear whether these subtypes employ similar or divergent oncogenic mechanisms. Here we used high throughput RNA sequencing and RNA interference screening to discover essential regulatory pathways that cooperate with MYC, the defining oncogene of this cancer. In 70% of sBL cases, mutations affecting the transcription factor TCF3 (E2A) or its negative regulator ID3 fostered TCF3 dependency. TCF3 activated the pro-survival PI(3) kinase pathway in BL, in part by augmenting tonic B cell receptor signaling. In 38% of sBL cases, oncogenic CCND3 mutations produced highly stable cyclin D3 isoforms that drive cell cycle progression. These findings suggest opportunities to improve therapy for patients with BL. Gene expression was analyzed using Agilent human 4X44K oligo gene expression arrays. Cell lines (Namalwa, BL41, Daudi, Defauw, and THOMAS) were infected with control (empty vector, Cy3) paired with ID3 (Cy5) or control (shControl, Cy3) paired with shTCF3 (Cy5) constructs, and changes in gene expression were monitored over time after induction of the constructs with doxycyclin. In Namalwa (n=8) and THOMAS (n=4) cell lines, a four timepoint series (24, 48, 72, 96 hours) of construct induction was analyzed, for a total of 12 arrays. In BL41 (n=4), Daudi (n=4) and Defauw (n=4) cell lines, a two timepoint series (24 and 48 hours) of construct induction was analyzed, for a total of 12 arrays. In addition, two cell lines (Daudi and THOMAS) were treated with Rapamycin (100 pM) and paired with a DMSO control in a four timepoint series (3, 6, 12 and 24 hours) for a total of 8 arrays.
2012-08-16 | E-GEOD-35163 | biostudies-arrayexpress
Project description:Recently global gene expression profiling of patients samples lead to a molecular definition of Burkitt Lymphoma (BL) with lymphocyte enhancer-binding factor 1 (LEF1) as a signature gene. Here we report the discovery of nucleic LEF1 in a very high proportion of BL cases (15/18) and LEF1 target genes. Germinal center B cells were devoid of detectable nuclear LEF1 expression as mantle cell lymphoma (0/5), marginal zone lymphoma (0/6), follicular lymphoma (0/12) or diffuse large B cell lymphoma (DLBCL) (1/31). Using whole genome gene expression profiling after transient knockdown of LEF1 in BL cell lines, new LEF1 target genes were identified. The joint expression of these genes in primary BL samples shows that LEF1 is not only expressed aberrantly in BL but also transcriptionally active. Our study identified aberrantly expressed LEF1 and its target genes suggesting an important functional role in BLs.
2013-06-01 | GSE42637 | GEO
Project description:Recently global gene expression profiling of patients samples lead to a molecular definition of Burkitt Lymphoma (BL) with lymphocyte enhancer-binding factor 1 (LEF1) as a signature gene. Here we report the discovery of nucleic LEF1 in a very high proportion of BL cases (15/18) and LEF1 target genes. Germinal center B cells were devoid of detectable nuclear LEF1 expression as mantle cell lymphoma (0/5), marginal zone lymphoma (0/6), follicular lymphoma (0/12) or diffuse large B cell lymphoma (DLBCL) (1/31). Using whole genome gene expression profiling after transient knockdown of LEF1 in BL cell lines, new LEF1 target genes were identified. The joint expression of these genes in primary BL samples shows that LEF1 is not only expressed aberrantly in BL but also transcriptionally active. Our study identified aberrantly expressed LEF1 and its target genes suggesting an important functional role in BLs. 3 biological replicates scrb siRNA vs LEF1 si RNA , 4 siRNA are pooled
2013-06-01 | E-GEOD-42637 | biostudies-arrayexpress
Project description:To identify genes mediating tumor transformation we compared the transcriptome of five Burkitt lymphoma (BL) cell lines (tumor cells) with that of a pool of three lymphoblastoid B-cell lines (LCL; immortal, but not tumor cells). Each BL cell line was considered as a biological replicate. BL cell lines: DG-75, Ramos, BL2, Mutu-I and Akata. LCL cell lines: X50-7, IB4 and Dana.
2015-09-30 | GSE41865 | GEO
Project description:By whole-genome, exome, transcriptome and methylome sequencing of four proto-typical Burkitt lymphomas (BL) with IG-MYC translocation we identified seven recurrently mutated genes including ID3. In an extended cohort, 36/53 (68%) molecularly-defined BL carried potentially damaging mutations of ID3 which were enriched at somatic hypermutation motifs. Only 6/47 (13%) other IG-MYC-positive B-cell lymphomas carried ID3 mutations suggesting cooperation of ID3 inactivation and IG-MYC translocation to be a hallmark of Burkitt lymphomagenesis.
| EGAS00001000271 | EGA
Project description:For sporadic Burkitt lymphoma (BL) few genetic lesions are known besides the pathognomonic IG-MYC translocations. Thirtynine molecularly-defined BL were analyzed with high-resolution single-nucleotide polymorphism chips for genomic imbalances and uniparental disomy (UPD). Imbalances were correlated to transcript profiling and selected miRNA analysis. Translocations affecting the MYC locus were studied by fluoresence in situ hybridization. We detected 528 copy number changes, defining 29 recurrently imbalanced regions. 518 regions of UPD were found, but these were rarely recurrent. Combined imbalance mapping and transcript profiling revealed a profound correlation between copy number and expression. Several recurrent imbalances affected the MYC pathway: The miRNA-supercluster 17-92 was frequently gained and the transcription factor E2F2 was recurrently deleted. Molecular BL lacking MYC translocations showed MYC gains. Amplifications of the polymerase iota gene were associated with increased genomic instability. The present findings suggests that UPDs play no major role in the pathogenesis of BL, whereas some genes may contribute to BL development through gene dosage effects. Amplifications of the polymerase iota gene may be functionally linked with increased genomic instability in BL. The pattern and rarity of chromosomal changes detectable even at the high resolution employed here, together with aberrations of genes regulating MYC activity, support that deregulation of the MYC pathway is the major force driving BL pathogenesis, but show that this deregulation is more complex than previously known. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from whole tissue. Copy number and LOH analysis of 500K SNP arrays was performed for 30 molecularly-defined Burkitt lymphomas. Genotyping was performed using the BRLMM-algorithm. Only a single 250k Chip was performed for nine additional Burkitts. 20 normal references (10 of those hybridized to nsp-chips) extracted from healthy blood donors, used as normals in the analysis in addition to the HapMap references provided by Affymetrix, are included in the set.
2010-12-07 | E-GEOD-21597 | biostudies-arrayexpress