IGHV mutational status of nodal marginal zone lymphoma by NGS reveals distinct pathogenic pathways with different prognostic implications

AbstractThe precise B cell of origin and molecular pathogenesis of nodal marginal zone lymphoma (NMZL) remain poorly defined. To date, due to the rarity of NMZL, the vast majority of already-published studies have been conducted on a limited number of samples and the technical approach to analyze the immunoglobulin genes was of amplifying rearranged variable region genes with the classical direct sequencing of the PCR products followed by cloning. Here, we studied the B cell Ig heavy-chain repertoires by next-generation sequencing (NGS) in 30 NMZL cases. Most of the cases were mutated (20/28; 71.5%) with homologies to the respective germ line genes ranging from 85 to 97, 83%, whereas 8/28 (28.5%) were unmutated. In addition, our results show that NMZL cases have a biased usage of specific immunoglobulin heavy-chain variable (IGHV) region genes. Moreover, we documented intraclonal diversity in all (100%) of the mutated cases and ongoing somatic hypermutations (SHM) have been confirmed by hundreds of reads. We analyzed the mutational pattern to detect and quantify antigen selection pressure and we found a positive selection in 4 cases, whereas in the remaining cases there was an unspecific stimulation. Finally, the disease-specific survival and the progression-free survival were significantly different between cases with mutated and unmutated IGHV genes, pointing out mutational status as a possible new biomarker in NMZL.

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Splenic marginal zone lymphoma: proposal of new diagnostic and prognostic markers identified after tissue and cDNA microarray analysis

Blood ◽

10.1182/blood-2004-10-3898 ◽

2005 ◽

Vol 106 (5) ◽

pp. 1831-1838 ◽

Cited By ~ 110

Author(s):

Elena Ruiz-Ballesteros ◽

Manuela Mollejo ◽

Antonia Rodriguez ◽

Francisca I. Camacho ◽

Patrocinio Algara ◽

...

Keyword(s):

B Cell ◽

Cdna Microarray ◽

Marginal Zone ◽

Prognostic Markers ◽

Variable Region ◽

Cell Receptor ◽

Marginal Zone Lymphoma ◽

Molecular Entity ◽

Splenic Marginal Zone Lymphoma ◽

Mutational Status

Abstract Splenic marginal zone lymphoma (SMZL) is a newly recognized lymphoma type whose precise molecular pathogenesis is still essentially unknown. This hampers differential diagnosis with other small B-cell malignancies. With the aim of characterizing this tumor more comprehensively, and of identifying new diagnostic and prognostic markers, we performed cDNA microarray expression profiling and tissue microarray (TMA) immunohistochemical studies in a relatively large series of 44 SMZLs. The results were related to immunoglobulin heavy chain variable region (IgVH) mutational status and clinical outcome. SMZLs display a largely homogenous signature, implying the existence of a single molecular entity. Of the genes deregulated in SMZLs, special mention may be made of the genes involved in B-cell receptor (BCR) signaling, tumor necrosis factor (TNF) signaling and nuclear factor-κB (NF-κB) activation, such as SYK, BTK, BIRC3, TRAF3, and LTB. Other genes observed were SELL and LPXN, which were highly expressed in spleen, and lymphoma oncogenes, such as ARHH and TCL1. In contrast, the genes CAV1, CAV2, and GNG11 located in 7q31, a commonly deleted area, were down-regulated in the entire series. A comparison with the genes comprising the signature of other small B-cell lymphomas identified 3 genes whose expression distinguishes SMZL, namely ILF1, SENATAXIN, and CD40. Shorter survival was associated with CD38 expression, naive IgVH genes, and the expression of a set of NF-κB pathway genes, including TRAF5, REL, and PKCA. (Blood. 2005;106:1831-1838)

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

Cancers ◽

10.3390/cancers12061669 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1669

Author(s):

Jiwon Koh ◽

Insoon Jang ◽

Seongmin Choi ◽

Sehui Kim ◽

Ingeon Jang ◽

...

Keyword(s):

B Cell ◽

High Throughput Sequencing ◽

Marginal Zone ◽

Progression Free Survival ◽

Cell Receptor ◽

Marginal Zone Lymphoma ◽

Ki 67 ◽

Genetic Characteristics ◽

Recurrent Mutations ◽

Nodal Marginal Zone Lymphoma

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-κB 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.

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EBV-positive nodal low-grade B-cell lymphoma with BCL3, IgA and IRTA1 expression: Is this a polymorphic lymphoproliferative disorder or an EBV-positive nodal marginal zone lymphoma?

Pathology International ◽

10.1111/pin.12687 ◽

2018 ◽

Vol 68 (9) ◽

pp. 538-540

Author(s):

Masakazu Fujimoto ◽

Yusuke Yamashita ◽

Hironori Haga ◽

Takashi Akasaka ◽

Yoshifumi Iwahashi ◽

...

Keyword(s):

B Cell ◽

Lymphoproliferative Disorder ◽

Marginal Zone ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Marginal Zone Lymphoma ◽

Low Grade ◽

Nodal Marginal Zone Lymphoma

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Absence of Mutations of the Histone Methyltransferase Gene EZH2 In Splenic B-Cell Marginal Zone Lymphoma

Blood ◽

10.1182/blood.v116.21.5086.5086 ◽

2010 ◽

Vol 116 (21) ◽

pp. 5086-5086

Author(s):

Luz Martínez-Avilés ◽

Marta Salido ◽

Beatriz Bellosillo ◽

Vera Adema ◽

Ana Ferrer ◽

...

Keyword(s):

B Cell ◽

Marginal Zone ◽

Mutational Analysis ◽

Conflicts Of Interest ◽

Direct Sequencing ◽

Normal Karyotype ◽

Marginal Zone Lymphoma ◽

Low Grade ◽

Splenic Marginal Zone Lymphoma ◽

7Q Deletion

Abstract Abstract 5086 Background Splenic marginal zone lymphoma (SMZL) is a rare low-grade B-cell lymphoproliferative disorder with characteristic clinical, cytological, histological and immunophenotypical features. The most common cytogenetic abnormality, present in 30–40% of the patients is the 7q deletion, that extends from 7q21 to 7q36. This aberration may represent a primary pathogenic event in SMZL. Recently, mutations in the EZH2 gene, located at 7q36.1, have been described in different hematological malignancies including B-cell lymphomas. However, the role of the EZH2 gene in SMZL has to be elucidated. Aim To determine the prevalence of EZH2 mutations in a cohort of SMZL patients. Patients and Methods Twenty-nine patients with SMZL were screened for mutations in the EZH2 gene. From the whole cohort, 11 patients presented 7q deletion (three of them as a single anomaly), 11 had a normal karyotype and 7 had other cytogenetic aberrations. The mutational analysis of the EZH2 gene was performed by direct sequencing using primers covering the whole exome of the gene. DNA was extracted from CD19 isolated B-cells from peripheral blood or from total lymphocytes if the percentage of pathologic B-cell was higher than 50%. Results From the whole cohort of 29 SMZL patients, no pathogenic mutations (frameshift or nonsense mutations) were detected in the EZH2 gene in any of the patients analyzed. Five patients harboured the missense mutation D185H in exon 6, that has been previously described as a single nucleotide polymorphism (SNP). Conclusions In conclusion, the EZH2 gene is not mutated in our series of SMZL patients suggesting that this gene is not involved in the pathogeny of this entity. Acknowledgments: Fellowship FI2008 (AGAUR) to LMA, This work was supported (in part) by grants from Instituto de Salud Carlos III FEDER; Red Temática de Investigación Cooperativa en Cáncer (RTICC, FEDER): RD06/0020/0031 and RD07/0020/2004; Ministerio de Sanidad y Consumo (Spain): PI07/0586. Disclosures: No relevant conflicts of interest to declare.

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Mutational Status of Splenic Marginal Zone Lymphoma Revealed by Whole Exome Sequencing.

Blood ◽

10.1182/blood.v120.21.2698.2698 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2698-2698

Author(s):

Nerea Martinez ◽

Ignacio Varela ◽

Jose P. Vaque ◽

Sophia Derdak ◽

Sergi Beltran ◽

...

Keyword(s):

B Cell ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Peripheral Blood ◽

Marginal Zone ◽

Marginal Zone Lymphoma ◽

Splenic Marginal Zone Lymphoma ◽

Mutational Status ◽

Whole Exome ◽

Splenic Tumor

Abstract Abstract 2698 Background: Splenic marginal zone lymphoma (SMZL) is a small B cell neoplasm whose molecular pathogenesis is still unknown. It has a relatively indolent course, but a fraction of the cases may show an aggressive behavior. The lack of comprehensive molecular analysis for SMZL precludes the development of targeted therapy. Here we studied the mutational status of 6 SMZL samples using Whole Exome Next Generation Sequencing. Methods: Genomic DNA was extracted from splenic tumor or peripheral blood samples and oral mucosa as the corresponding non-tumor control. Whole exome sequencing was performed at CNAG (Barcelona, Spain) following standard protocols for high-throughput paired-end sequencing on the Illumina HiSeq2000 instruments (Illumina Inc., San Diego, CA). The variant calling was performed using an in house written software calling potential mutations showing a minimum independent multi-aligner evidence. Results: We performed paired-end-76pb whole exome sequencing on 6 SMZL samples and the corresponding normal counterpart. Three of the samples corresponded to CD19 isolated cells from peripheral blood, while other three corresponded to spleen freshly frozen tissue. The mean coverage obtained was 104.07 (82.46–119.59) with a mean of 91.41% (90.41–93.73) of bases with at least 15× coverage. After filtering, 237 substitutions and 21 indels where obtained. No recurrent variation was found. Six of the variations found here were already described in other malignancies. Variations were classified into silent (75), missense (147), nonsense (8), and essential splice (5), according to their potential functional effect, and into tolerated (54) and deleterious (76) according to the “variant effect predictor” tool of Ensembl Genome Browser. Whole exome sequencing permitted us to identify variations in several genes of TLR/NFkB pathway (Myd88, Peli3), BCR (Myd88, Arid3A) or signal transduction (ARHGAP32), essential pathways for B-cell differentiation. These variations and other involving selected genes, such as the Bcl6 repressor BCOR, were validated by capillary sequencing. These results were confirmed and expanded in a second series of 10 new cases by exome sequencing. Conclusions: SMZL samples contain somatic mutation involving genes regulating BCR signaling, TLR/NFKB pathways and chromatin remodeling. Disclosures: No relevant conflicts of interest to declare.

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The genetics of nodal marginal zone lymphoma

Blood ◽

10.1182/blood-2016-02-696757 ◽

2016 ◽

Vol 128 (10) ◽

pp. 1362-1373 ◽

Cited By ~ 68

Author(s):

Valeria Spina ◽

Hossein Khiabanian ◽

Monica Messina ◽

Sara Monti ◽

Luciano Cascione ◽

...

Keyword(s):

B Cell ◽

Marginal Zone ◽

Marginal Zone Lymphoma ◽

Key Points ◽

Nodal Marginal Zone Lymphoma ◽

Lymphoma Type

Key Points PTPRD lesions are among the most recurrent alterations in NMZL and appear to be enriched in this lymphoma type across mature B-cell tumors. NMZL and SMZL genetics overlap with the exceptions of PTPRD lesions, supporting their distinction as independent entities.

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Correction to: IGHV mutational status of nodal marginal zone lymphoma by NGS reveals distinct pathogenic pathways with different prognostic implications

Virchows Archiv ◽

10.1007/s00428-020-02794-9 ◽

2020 ◽

Vol 477 (1) ◽

pp. 169-169

Author(s):

Massimo Granai ◽

Teresa Amato ◽

Arianna Di Napoli ◽

Raffaella Santi ◽

Federica Vergoni ◽

...

Keyword(s):

Marginal Zone ◽

Marginal Zone Lymphoma ◽

Mutational Status ◽

Prognostic Implications ◽

Nodal Marginal Zone Lymphoma

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Somatic hypermutation of immunoglobulin heavy chain variable region genes in thymic marginal zone B-cell lymphoma of MALT type of a patient with Sjogren's syndrome

Histopathology ◽

10.1046/j.1365-2559.2002.1363b.x ◽

2002 ◽

Vol 40 (3) ◽

pp. 294-296 ◽

Cited By ~ 18

Author(s):

K Kamimura ◽

N Nakamura ◽

T Ishibashi ◽

Y Maruyama ◽

M Abe

Keyword(s):

B Cell ◽

Heavy Chain ◽

Marginal Zone ◽

Cell Lymphoma ◽

Somatic Hypermutation ◽

Variable Region ◽

B Cell Lymphoma ◽

Immunoglobulin Heavy Chain ◽

Heavy Chain Variable Region ◽

Variable Region Genes

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Nodal marginal zone lymphoma: gene expression and miRNA profiling identify diagnostic markers and potential therapeutic targets

Blood ◽

10.1182/blood-2011-02-339556 ◽

2012 ◽

Vol 119 (3) ◽

pp. e9-e21 ◽

Cited By ~ 59

Author(s):

Alberto J. Arribas ◽

Yolanda Campos-Martín ◽

Cristina Gómez-Abad ◽

Patrocinio Algara ◽

Margarita Sánchez-Beato ◽

...

Keyword(s):

Gene Expression ◽

B Cell ◽

Marginal Zone ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Marginal Zone Lymphoma ◽

Survival Pathways ◽

Gene Sets ◽

Nodal Marginal Zone Lymphoma ◽

Follicular Lymphomas

Abstract Nodal marginal zone lymphoma (NMZL) is a small B-cell neoplasm whose molecular pathogenesis is still essentially unknown and whose differentiation from other small B-cell lymphomas is hampered by the lack of specific markers. We have analyzed gene expression, miRNA profile, and copy number data from 15 NMZL cases. For comparison, 16 follicular lymphomas (FLs), 9 extranodal marginal zone lymphomas, and 8 reactive lymph nodes and B-cell subtypes were included. The results were validated by quantitative RT-PCR in an independent series, including 61 paraffin-embedded NMZLs. NMZL signature showed an enriched expression of gene sets identifying interleukins, integrins, CD40, PI3K, NF-κB, and TGF-β, and included genes expressed by normal marginal zone cells and memory B cells. The most highly overexpressed genes were SYK, TACI, CD74, CD82, and CDC42EP5. Genes linked to G2/M and germinal center were down-regulated. Comparison of the gene expression profiles of NMZL and FL showed enriched expression of CHIT1, TGFB1, and TACI in NMZL, and BCL6, LMO2, and CD10 in FL. NMZL displayed increased expression of miR-221, miR-223, and let-7f, whereas FL strongly expressed miR-494. Our study identifies new candidate diagnostic molecules for NMZL and reveals survival pathways activated in NMZL.

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