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Analysis of the coding exome of follicular lymphoma

ABSTRACT: Follicular lymphoma (FL) constitutes the second most common non-Hodgkin lymphoma in the Western world. FL carries characteristic recurrent structural genomic aberrations. However, information regarding the coding genome in FL is still evolving. Here, we describe the results of massively parallel exome sequencing and high-resolution SNP 6.0 array profiling of 12 highly purified FL cases and validation of mutations in an expansion cohort of 45 cases. In addition to confirming high-frequency mutations in MLL2, CREBBP and BCL2, we report identification of 18 recurrently mutated genes in FL. These include novel mutations in MCL1, IRF8 and POU2FA/OCT2, and high-frequency mutations in various components of the linker histone HIST1H1. Further, multiple novel mutated genes located within regions of acquired uniparental disomy (aUPD) are identified, providing candidate genes for this common lesion type in FL. In aggregate, these data substantially broaden our understanding of the types and frequency of recurrently mutated genes and pathways in FL

ORGANISM(S): Homo sapiens

PROVIDER: GSE50973 | GEO | 2014/01/17

SECONDARY ACCESSION(S): PRJNA221350

REPOSITORIES: GEO

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Analysis of the coding exome of follicular lymphoma

Project description:Follicular lymphoma (FL) constitutes the second most common non-Hodgkin lymphoma in the Western world. FL carries characteristic recurrent structural genomic aberrations. However, information regarding the coding genome in FL is still evolving. Here, we describe the results of massively parallel exome sequencing and high-resolution SNP 6.0 array profiling of 12 highly purified FL cases and validation of mutations in an expansion cohort of 45 cases. In addition to confirming high-frequency mutations in MLL2, CREBBP and BCL2, we report identification of 18 recurrently mutated genes in FL. These include novel mutations in MCL1, IRF8 and POU2FA/OCT2, and high-frequency mutations in various components of the linker histone HIST1H1. Further, multiple novel mutated genes located within regions of acquired uniparental disomy (aUPD) are identified, providing candidate genes for this common lesion type in FL. In aggregate, these data substantially broaden our understanding of the types and frequency of recurrently mutated genes and pathways in FL Twelve paired normal and tumor follicular lymphoma cases were profiled by SNP array for this study. However, in addition the data from 125 CEL files derived from the DNA of flow-sorted CD3+ cells from 125 CLL patients (122 CEL files from GSE30777) were used to firmly establish a normal copy number baseline for the dChip software to compute all subsequent normal and tumor DNA copy number values.

2014-01-17 | E-GEOD-50973 | biostudies-arrayexpress

Gene expression Profiling in Follicular Lymphomas

Project description:Follicular lymphoma (FL) is an indolent, but incurable subtype of non-Hodgkin lymphoma. These tumor harbor t (14;18) translocation in at least 90% of patients. Recently, activating EZH2 mutations have been Follicular lymphoma (FL) is an indolent, but incurable subtype of non-Hodgkin lymphoma. These tumor harbor t (14;18) translocation in at least 90% of patients. Recently, activating EZH2 mutations have been found in a significant number of patients with FL. Gene expression profiling (GEP) was performed to determine differential gene-expression between the EZH2 mutated vs unmutated subgroups in FL. Total RNA extracted from fresh frozen specimens with FL diagnosis were processed for hybridization to Affymetrix HG-U133 plus 2 arrays. To enhance the identification of differential gene expression in FL tumor cells only, FL cases with a high B-cell content (enriched B-cell signature of >2-fold above the mean of the B-cell signature (pan B-cell markers) in the entire FL data set) were chosen for analysis.

2014-07-01 | E-GEOD-55267 | biostudies-arrayexpress

Regions of acquired UPD at diagnosis of FL are associated with both overall survival and risk of transformation

Project description:SNP array analysis was performed using the Affymetrix 10K 2.0 Gene-chip array on DNA from 181 diagnostic Follicular Lymphoma (FL) patients to assess the prognostic relevance of aUPD. Genetic abnormalities were detected in 118/181 (65%) patients. Number of abnormalities was predictive of outcome; > 3 abnormalities was associated with inferior overall survival (OS) (p<0.03). Sites of recurrent aUPD were detected on 6p (n=25), 16p (n=22), 12q (n=17), 1p36 (n=14), 10q (n=8) and 6q (n=8). On multivariate analysis aUPD 1p36 correlated with shorter OS (p=0.05). aUPD 16p was predictive of transformation (p=0.03) and correlated with poorer progression free survival (p=0.02). Keywords: Genomic analysis of FL samples

2009-01-30 | GSE14582 | GEO

Expression of TCF3 target genes defines a subclass of diffuse large B-cell lymphoma characterized by up-regulation of MYC target genes and poor clinical outcome following R-CHOP therapy

Project description:Fifty-eight retrospectively-ascertained local cases of diffuse large B-cell lymphoma (DLBCL) were segregated into two large subgroups with divergent overall survival through expression profiling of 135 transcripts including 92 regulated downstream of TCF3 or recurrently mutated in DLBCL or Burkitt lymphoma

2022-11-10 | GSE212114 | GEO

Sequencing Follicular Lymphoma

Project description:<p>We performed exome sequencing of tumor (lymph node) and normal (skin) frozen tissue pairs from 24 patients in a discovery cohort with untreated follicular lymphoma (FL), relapsed FL, or transformed FL/iNHL (indolent non-Hodgkin lymphoma). From 24 patients, 28 tumor samples were exome sequenced including 1 patient with both untreated and relapse samples and 3 patients with samples derived from both bulk lymph node and following flow-sorting to purify light chain-restricted CD19+ lymphoma cells. We developed a custom capture assay (NimbleGen) that targets 7.05 MB corresponding to the exons and splice sites of 1716 genes (WUSM-LP). The custom capture genes included somatic nucleotide variants (SNVs) identified in our exome discovery cohort (898 genes) or SNVs previously published to be recurrently mutated in B cell NHL (818 genes). This custom capture reagent was used to sequence additional FFPE samples (and corresponding normal tissue, when available) from patients with follicular lymphoma. This approach was used to identify recurrently mutated genes in pathways in FL.</p>

| phs001229 | dbGaP

Genotyping of human diagnostic Follicular Lymphoma (FL) patients to assess the prognostic relevance of aUPD reveals regions of acquired UPD at diagnosis of FL are associated with both overall survival and risk of transformation

2009-02-09 | E-GEOD-14582 | biostudies-arrayexpress

Gene expression Profiling in Follicular Lymphomas

2014-07-01 | GSE55267 | GEO

Integrative profiling of follicular lymphoma at diagnosis and relapse

Project description:Follicular lymphoma (FL) is incurable with conventional therapies and has a clinical course typified by multiple relapses after therapy. These tumors are genetically characterized by B-cell leukemia/lymphoma 2 (BCL2) translocation and mutation of genes involved in chromatin modification. By analyzing purified tumor cells, we identified additional novel recurrently mutated genes and confirmed mutations of one or more chromatin modifier genes within 96% of FL tumors and two or more in 76% of tumors. We defined the hierarchy of somatic mutations arising during tumor evolution by analyzing the phylogenetic relationship of somatic mutations across the coding genomes of 59 sequentially acquired biopsies from 22 patients. Among all somatically mutated genes, CREBBP mutations were most significantly enriched within the earliest inferable progenitor. These mutations were associated with a signature of decreased antigen presentation characterized by reduced transcript and protein abundance of MHC class II on tumor B cells, in line with the role of CREBBP in promoting class II transactivator (CIITA)-dependent transcriptional activation of these genes. CREBBP mutant B cells stimulated less proliferation of T cells in vitro compared with wild-type B cells from the same tumor. Transcriptional signatures of tumor-infiltrating T cells were indicative of reduced proliferation, and this corresponded to decreased frequencies of tumor-infiltrating CD4 helper T cells and CD8 memory cytotoxic T cells. These observations therefore implicate CREBBP mutation as an early event in FL evolution that contributes to immune evasion via decreased antigen presentation.

2015-03-02 | GSE56311 | GEO

Follicular lymphoma in situ and partial involvement by follicular lymphoma are clona lesions that carry the t(14;18) and lack genetic secondary alterations

Project description:Follicular lymphoma (FL) is characterized by the t(14;18)(q32;q21), frequent numerical chromosomal alterations, and recurrent somatic mutations. However, no genetic studies are available for FL in situ (FLIS), a putative precursor lesion of FL. In this study, we analyzed cases of FLIS without manifest (m)FL, partial involvement by FL (PFL), and paired cases of FLIS and mFL to detect possible early chromosomal imbalances, as well as DNA-methylation patterns of genomic regions of selected genes. We demonstrated that paired FLIS and mFL cases are always clonally related. FLIS and PFL have no or few secondary chromosomal imbalances detectable by copy number arrays and a lower level of gene methylation as compared to mFL. Additionally, EZH2 Tyr641 mutations were detected in a subset of both FLIS and PFL cases. In conclusion, this study provides evidence that FLIS represents a FL precursor lesion of long-lived clonal B-cells carrying the t(14;18) with no or few secondary genetic changes. The earliest secondary genetic alterations detected in FLIS are the EZH2 Tyr641 mutation and low levels of CNAs, as evidence of clonal evolution. Our data suggest that there may be more than one distinct lesion driving the progression from FLIS to manifest lymphoma. DNA from cases, 20 tumor samples (10 in situ Follicular lymphoma, 4 Partial infiltration folliculary lymphoma and 6 manifest FL) were analyzed with Agilent-014693 Human Genome CGH Microarray 244A platform for copy number alterations study. For cases 9-14 paired samples of in situ follicular lymphoma and manifest follicular lymphoma were analyzed. Agilent-014693 Human Genome CGH Microarray 244A arrays were performed according to the manufacturer's directions on DNA extracted from lymph nodes that were hybridized against a normal DNA (pool) of the same gender.

2013-11-12 | E-GEOD-48548 | biostudies-arrayexpress

Follicular lymphoma in situ and partial involvement by follicular lymphoma are clona lesions that carry the t(14;18) and lack genetic secondary alterations

2013-11-12 | GSE48548 | GEO

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