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High-throughput sequencing of nodal marginal zone lymphomas identifies recurrent BRAF mutations.

ABSTRACT: Nodal marginal zone lymphoma (NMZL) is a rare small B-cell lymphoma lacking disease-defining phenotype and precise diagnostic markers. To better understand the mutational landscape of NMZL, particularly in comparison to other nodal small B-cell lymphomas, we performed whole-exome sequencing, targeted high-throughput sequencing, and array-comparative genomic hybridization on a retrospective series. Our study identified for the first time recurrent, diagnostically useful, and potentially therapeutically relevant BRAF mutations in NMZL. Sets of somatic mutations that could help to discriminate NMZL from other closely related small B-cell lymphomas were uncovered and tested on unclassifiable small B-cell lymphoma cases, in which clinical, morphological, and phenotypical features were equivocal. Application of targeted gene panel sequencing gave at many occasions valuable clues for more specific classification.

SUBMITTER: Pillonel V

PROVIDER: S-EPMC6224405 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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High-throughput sequencing of nodal marginal zone lymphomas identifies recurrent BRAF mutations.

Pillonel V V Juskevicius D D Ng C K Y CKY Bodmer A A Zettl A A Jucker D D Dirnhofer S S Tzankov A A

Leukemia 20180228 11

Nodal marginal zone lymphoma (NMZL) is a rare small B-cell lymphoma lacking disease-defining phenotype and precise diagnostic markers. To better understand the mutational landscape of NMZL, particularly in comparison to other nodal small B-cell lymphomas, we performed whole-exome sequencing, targeted high-throughput sequencing, and array-comparative genomic hybridization on a retrospective series. Our study identified for the first time recurrent, diagnostically useful, and potentially therapeut ...[more]

PMID: 29556019

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Whole-genome sequencing identifies recurrent somatic NOTCH2 mutations in splenic marginal zone lymphoma.

Project description:Splenic marginal zone lymphoma (SMZL), the most common primary lymphoma of spleen, is poorly understood at the genetic level. In this study, using whole-genome DNA sequencing (WGS) and confirmation by Sanger sequencing, we observed mutations identified in several genes not previously known to be recurrently altered in SMZL. In particular, we identified recurrent somatic gain-of-function mutations in NOTCH2, a gene encoding a protein required for marginal zone B cell development, in 25 of 99 (∼25%) cases of SMZL and in 1 of 19 (∼5%) cases of nonsplenic MZLs. These mutations clustered near the C-terminal proline/glutamate/serine/threonine (PEST)-rich domain, resulting in protein truncation or, rarely, were nonsynonymous substitutions affecting the extracellular heterodimerization domain (HD). NOTCH2 mutations were not present in other B cell lymphomas and leukemias, such as chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 15), mantle cell lymphoma (MCL; n = 15), low-grade follicular lymphoma (FL; n = 44), hairy cell leukemia (HCL; n = 15), and reactive lymphoid hyperplasia (n = 14). NOTCH2 mutations were associated with adverse clinical outcomes (relapse, histological transformation, and/or death) among SMZL patients (P = 0.002). These results suggest that NOTCH2 mutations play a role in the pathogenesis and progression of SMZL and are associated with a poor prognosis.

| S-EPMC3428949 | biostudies-literature

Discovery of Novel Recurrent Mutations and Clinically Meaningful Subgroups in Nodal Marginal Zone Lymphoma.

Project description:Nodal marginal zone lymphoma (NMZL) is a rare B-cell neoplasm, the genetic and transcriptomic landscape of which are unclear. Using high-throughput sequencing for whole-exome and transcriptome, we investigated the genetic characteristics of NMZL in a discovery cohort (n = 8) and validated their features in an extended cohort (n = 30). Novel mutations in NFKBIE and ITPR2 were found in 7.9% (3/38) and 13.9% (5/36), respectively, suggesting roles for the NF-?B pathway and B-cell-receptor-mediated calcium signaling pathway in the pathogenesis of NMZL. RNA-seq showed that NMZLs were characterized by an aberrant marginal zone differentiation, associated with an altered IRF4-NOTCH2 axis and the enrichment of various oncogenic pathways. Based on gene expression profile, two subgroups were identified. Compared with subgroup 1, subgroup 2 showed the following: the significant enrichment of cell cycle-associated and MYC-signaling pathways, a more diverse repertoire of upstream regulators, and higher Ki-67 proliferation indices. We designated two subgroups according to Ki-67 labeling, and subgroup 2 was significantly associated with a shorter progression-free survival (p = 0.014), a greater proportion of large cells (p = 0.009), and higher MYC expression (p = 0.026). We suggest that NMZL has unique features and, in this study, we provide information as to the heterogeneity of this enigmatic entity.

| S-EPMC7352856 | biostudies-literature

Recurrent mutations in NF-?B pathway components, KMT2D, and NOTCH1/2 in ocular adnexal MALT-type marginal zone lymphomas.

Project description:The pathogenesis of ocular adnexal marginal zone lymphomas of mucosa-associated lymphatic tissue-type (OAML) is still poorly understood. We analyzed 63 cases of such lymphomas for non-synonymous mutations in 24 candidate genes by amplicon sequencing. We validated frequent mutations in the NF-?B regulators MYD88, TNFAIP3 and TNIP1 in OAML, but also identified recurrent mutations in several additional components of the NF-?B pathway, including BCL10 and NFKBIA. Overall, 60% of cases had mutations in at least one component of NF-?B signaling, pointing to a central role of its genetic deregulation in OAML pathogenesis. Mutations in NOTCH1 and NOTCH2 were each found in 8% of cases, indicating a pathogenetic function of these factors in OAML. KMT2D was identified as the first epigenetic regulator with mutations in OAML, being mutated in 22% of cases. Mutations in MYD88 were associated with an inferior disease-free survival. Overall, we identified here highly recurrent genetic lesions in components of the NF-?B pathway, of NOTCH1 and NOTCH2 as well as KMT2D in OAML and thereby provide major novel insights into the pathogenesis of this B cell malignancy.

| S-EPMC5308752 | biostudies-literature

Incidence and subtype specificity of API2-MALT1 fusion translocations in extranodal, nodal, and splenic marginal zone lymphomas.

Project description:The t(11;18)(q21;q21) is thought to represent an important primary event in the development of marginal zone lymphomas, although an accurate estimation of the frequency and distribution of this genetic alteration among nodal, splenic, and extranodal marginal zone lymphoma types has yet to be determined. Recently, molecular genetic studies have shown that this translocation results in the fusion of the API2 gene on chromosome 11 and a novel gene termed MALT1 on chromosome 18. To investigate the incidence of API2-MALT1 fusion transcripts among marginal zone lymphomas and to determine possible marginal zone lymphoma subtype associations, we used reverse transcriptase-polymerase chain reaction to analyze RNAs extracted from frozen tissue samples of 99 marginal zone lymphomas. Fifty-seven involved diverse extranodal sites including 14 stomach, 11 lung, 7 orbit, 7 parotid, 5 thyroid, 5 lacrimal gland, 3 small intestine, 2 large intestine, 1 kidney, 1 paraspinal region and 1 skin. Twenty-one primary splenic and twenty-one primary nodal marginal zone lymphomas were also studied. API2-MALT1 fusion transcripts were detected in 12 of 57 extranodal marginal zone lymphomas (21%), but in none of the nodal or splenic cases. The cDNA sequences of the fusion transcripts were determined, revealing variation in the coding sequence fusion point for both API2 and MALT1. The findings suggest that t(11;18)(q21;q21) is restricted to extranodal marginal zone lymphomas and that these tumors have distinct genetic etiologies in comparison with their splenic and nodal counterparts.

| S-EPMC1876902 | biostudies-literature

The genetics of nodal marginal zone lymphoma.

Project description:Nodal marginal zone lymphoma (NMZL) is a rare, indolent B-cell tumor that is distinguished from splenic marginal zone lymphoma (SMZL) by the different pattern of dissemination. NMZL still lacks distinct markers and remains orphan of specific cancer gene lesions. By combining whole-exome sequencing, targeted sequencing of tumor-related genes, whole-transcriptome sequencing, and high-resolution single nucleotide polymorphism array analysis, we aimed at disclosing the pathways that are molecularly deregulated in NMZL and we compare the molecular profile of NMZL with that of SMZL. These analyses identified a distinctive pattern of nonsilent somatic lesions in NMZL. In 35 NMZL patients, 41 genes were found recurrently affected in ≥3 (9%) cases, including highly prevalent molecular lesions of MLL2 (also known as KMT2D; 34%), PTPRD (20%), NOTCH2 (20%), and KLF2 (17%). Mutations of PTPRD, a receptor-type protein tyrosine phosphatase regulating cell growth, were enriched in NMZL across mature B-cell tumors, functionally caused the loss of the phosphatase activity of PTPRD, and were associated with cell-cycle transcriptional program deregulation and increased proliferation index in NMZL. Although NMZL shared with SMZL a common mutation profile, NMZL harbored PTPRD lesions that were otherwise absent in SMZL. Collectively, these findings provide new insights into the genetics of NMZL, identify PTPRD lesions as a novel marker for this lymphoma across mature B-cell tumors, and support the distinction of NMZL as an independent clinicopathologic entity within the current lymphoma classification.

| S-EPMC5016706 | biostudies-literature

A20 IN MARGINAL ZONE LYMPHOMAS

Project description:Unique and shared cytogenetic abnormalities have been documented for marginal zone lymphomas (MZLs) arising at different sites. Recently, homozygous deletions of the chromosomal band 6q23, involving the tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20) gene, a negative regulator of NF-kappa B, were described in ocular adnexal MZL, suggesting a role for A20 as a tumor suppressor in this disease entity. Here, we investigated inactivation of A20 by DNA mutations or deletions in a panel of extranodal (EMZL), nodal (NMZL) and splenic (SMZL) MZLs. Inactivating mutations encoding truncated A20 proteins were identified in 6/32 (18.8%) MZLs, including 3/11 (27.3%) EMZLs, 2/9 (22.2%) NMZLs, and 1/12 (8.3%) SMZLs. Two additional unmutated non-splenic MZLs also showed mono- or biallelic A20 deletions by FISH and/or array-CGH. Thus, A20 loss by both somatic mutations and/or deletions represents a common genetic aberration across all MZL subtypes, which may contribute to lymphomagenesis by inducing constitutive NF-kappa B activation. Keywords: Genome variation profiling by SNP array

2009-04-01 | GSE13989 | GEO

A20 IN MARGINAL ZONE LYMPHOMAS

2009-04-01 | E-GEOD-13989 | biostudies-arrayexpress

The genetic landscape of dural marginal zone lymphomas.

Project description:The dura is a rare site of involvement by marginal zone lymphoma (MZL) and the biology of dural MZL is not well understood. We performed genome-wide DNA copy number and targeted mutational analysis of 14 dural MZL to determine the genetic landscape of this entity. Monoallelic and biallelic inactivation of TNFAIP3 by mutation (n=5) or loss (n=1) was observed in 6/9 (67%) dural MZL exhibiting plasmacytic differentiation, including 3 IgG4+ cases. In contrast, activating NOTCH2 mutations were detected in 4/5 (80%) dural MZL displaying variable monocytoid morphology. Inactivating TBL1XR1 mutations were identified in all NOTCH2 mutated cases. Recurrent mutations in KLHL6 (n=2) and MLL2 (n=2) were also detected. Gains at 6p25.3 (n=2) and losses at 1p36.32 (n=3) were common chromosomal imbalances, with loss of heterozygosity (LOH) of these loci observed in a subset of cases. Translocations involving the IGH or MALT1 genes were not identified. Our results indicate genetic similarities between dural MZL and other MZL subtypes. However, recurrent and mutually exclusive genetic alterations of TNFAIP3 and NOTCH2 appear to be associated with distinct disease phenotypes in dural MZL.

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Molecular characterization of Nodal marginal zone lymphoma

Project description:This SuperSeries is composed of the following subset Series: GSE32231: Molecular characterization of Nodal marginal zone lymphoma [Gene Expression] GSE32232: microRNA-expression profile in a series of Nodal marginal zone lymphoma patients [miRNA expression] Refer to individual Series

2011-09-20 | E-GEOD-32233 | biostudies-arrayexpress

Molecular characterization of Nodal marginal zone lymphoma

Project description:This SuperSeries is composed of the SubSeries listed below.

2011-09-21 | GSE32233 | GEO