Analysis of the IgVH somatic mutations in splenic marginal zone lymphoma defines a group of unmutated cases with frequent 7q deletion and adverse clinical course

Algara, Patricia; Mateo, Marisol; Sánchez‐Beato, Margarita; Mollejo, Manuela; Navas, Immaculada C.; Romero, Lourdes; Solé, Françesc; Salido, Marta; Florensa, Lourdes; Martı́nez, Pedro; Campo, Elı́as; Piris, Miguel Á.

doi:10.1182/blood.v99.4.1299

Cited by 157 publications

(145 citation statements)

References 36 publications

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“…VH3-23 and VH3-30 have been closely associated with autoimmune disease, with the former found in patients with autoimmune thrombocytopenia, 28,29 Graves' disease, 30 and Wegener's granulomatosis, 31 and the latter in patients with systemic lupus erythematosus, 29 autoimmune thrombocytopenia, 28 and Kawasaki's disease. 32 In contrast, a biased usage of particular VH fragments has been reported in chronic lymphoid leukemia (VH3-21), 14,15 splenic marginal zone lymphoma (VH1-2), 16 and salivary MALT lymphoma (VH1-69). 17 We have reported recently that VH3-23 and VH3-30 have been frequently used in thymic MALT lymphoma, a tumor closely associated with autoimmune disease.…”

Section: Discussionmentioning

confidence: 99%

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Immunoglobulin VH gene analysis in gastric MALT lymphomas

et al. 2007

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The majority of gastric mucosa-associated lymphoid tissue (MALT) lymphomas are successfully treated with Helicobacter pylori eradication alone. However, certain subsets of these tumors are resistant to the eradication treatment. As API2-MALT1 fusion is a feature of one of these subsets, we divided gastric MALT lymphomas into three groups: eradication-responsive and API2-MALT1 fusion-negative (Group A), eradication-resistant and fusion-negative (Group B), and eradication-resistant and fusion-positive (Group C). To characterize further gastric MALT lymphomas, we analyzed VH genes, which do not change in the course of tumor progression, by extensive subcloning of the monoclonal PCR products of 45 cases. VH3-23 and VH3-30 were preferentially used in Group A tumors (14/23 cases, 61%) as compared with Group B (1/10 cases, 10%, P ¼ 0.0094) and Group C (2/ 12 cases, 17%, P ¼ 0.017). Tumors of Groups B and C used variegated VH fragments, and no dominant VH fragments were noted. Somatic mutation was detected in most of the cases. Ongoing mutation was detected in 3/45 cases (7%), when assessed according to strict criteria for a confirmed mutation. These findings suggest that inflammation-dependent tumors (Group A) may be derived from a highly restricted, probably H. pyloriassociated, B cell subset and may not often progress to those that are inflammation-independent (Groups B and C). Although considered to be common in this tumor, ongoing mutation may be infrequent when assessed by strict criteria. Keywords: gastric MALT lymphoma; helicobacter pylori; eradication; immunoglobulin heavy chain variable genes; API2-MALT1 fusion gene Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) is a distinct low-grade lymphoma, which is typically localized long term at the site of origin. 1 A preexisting chronic inflammation, such as Helicobacter pylori gastritis, Hashimoto's thyroiditis, or Sjogren's syndrome is considered to influence significantly its development. 1 The etiological link between gastric MALT lymphoma and H. pylori gastritis has arisen from the fact that the majority of gastric MALT lymphomas (approximately 70% of cases) show complete regression on eradication of H. pylori alone. 2 API2-MALT1 fusion, cloned from t(11;18)(q21;q21), is a gene alteration specific to MALT lymphomas. 3,4 API2 is a member of the IAP (inhibitor of apoptosis) gene family, and is essential for the suppression of apoptosis. 5 MALT1, a novel

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Section: Discussionmentioning

confidence: 99%

“…12,13 A biased usage of particular VH segments has been reported in chronic lymphoid leukemia, 14,15 splenic marginal zone lymphoma, 16 and MALT lymphomas of the salivary gland 17 and thymus. 18 Although gastric MALT lymphoma has been studied more intensively than MALT lymphomas in other sites, its VH gene usage has not been well characterized.…”

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confidence: 99%

Immunoglobulin VH gene analysis in gastric MALT lymphomas

et al. 2007

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“…1 Some cytogenetic, molecular and clinical information has been reported previously. 10,13,16,22 The study was conducted in accordance with the Declaration of Helsinki and approved by the local Ethics Committee of each institution.…”

Section: Patient Groupmentioning

confidence: 99%

“…21 Furthermore, some studies have also examined whether particular molecular characteristics of the IG receptors might be associated with genetic or phenotypic features, and/or clinical outcome. However, owing to their retrospective nature, definitive conclusions cannot be drawn, except possibly for certain genomic aberrations, which have been detected with higher frequency among IGHV-unmutated cases (especially, deletion of chromosome 7q 10,20,22 and/or cases expressing particular IGHV genes). 20,22 With few exceptions, 21,22 most relevant publications have been based on the analysis of relatively small series.…”

Section: Introductionmentioning

confidence: 99%

Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications

et al. 2012

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We performed an immunogenetic analysis of 345 IGHV --IGHD --IGHJ rearrangements from 337 cases with primary splenic small B-cell lymphomas of marginal-zone origin. Three immunoglobulin (IG) heavy variable (IGHV) genes accounted for 45.8% of the cases (IGHV1-2, 24.9%; 12.8%; 8.1%). Particularly for the IGHV1-2 gene, strong biases were evident regarding utilization of different alleles, with 79/86 rearrangements (92%) using allele *04. Among cases more stringently classified as splenic marginal-zone lymphoma (SMZL) thanks to the availability of splenic histopathological specimens, the frequency of IGHV1-2*04 peaked at 31%. The IGHV1-2*04 rearrangements carried significantly longer complementaritydetermining region-3 (CDR3) than all other cases and showed biased IGHD gene usage, leading to CDR3s with common motifs. The great majority of analyzed rearrangements (299/345, 86.7%) carried IGHV genes with some impact of somatic hypermutation, from minimal to pronounced. Noticeably, 75/79 (95%) IGHV1-2*04 rearrangements were mutated; however, they mostly (56/75 cases; 74.6%) carried few mutations (97 --99.9% germline identity) of conservative nature and restricted distribution. These distinctive features of the IG receptors indicate selection by (super)antigenic element(s) in the pathogenesis of SMZL. Furthermore, they raise the possibility that certain SMZL subtypes could derive from progenitor populations adapted to particular antigenic challenges through selection of VH domain specificities, in particular the IGHV1-2*04 allele.

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“…The PCR conditions have been described previously. 23 Each PCR product was subsequently cloned. Gelpurified PCR products from these cases were ligated into a PGEM-T easy vector (Promega).…”

Section: Igv H Studymentioning

confidence: 99%

IgV and bcl6 somatic mutation analysis reveals the heterogeneity of cutaneous B-cell lymphoma, and indicates the presence of undisclosed local antigens

et al. 2004

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Our understanding of the ontology of B-cell lymphomas (BCL) has been improved by the study of mutational status of IgV H and bcl6 genes, but only a few cases of cutaneous BCL have been examined for this status. We analyzed IgV H and bcl6 somatic mutations in 10 cutaneous BCL, classified as follicular (three primary and one secondary), primary marginal zone (two cases), and diffuse large BCL (three primary and one secondary). We observed a lower rate (o2%) of IgV H mutation in all marginal zone lymphomas, and a preferential usage of V H 2-70 (one primary follicular and two primary diffuse large BCL). Fewer than expected replacement mutations in framework regions (FR) were observed in three primary follicular lymphomas (FLs) and in all diffuse large BCL, indicating a negative antigen selection pressure. Ongoing mutations were observed in eight of 10 cases. Only two primary FLs and two diffuse large BCL showed bcl6 somatic mutation. These data support the heterogeneous nature of the different cutaneous BCL, and specifically the distinction between cutaneous follicular and marginal zone lymphomas. The biased usage of V H 2-70, the low rate of replacement mutation in the FR, and the presence of ongoing mutation imply that local antigens could modulate the growth of primary cutaneous BCL.

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Analysis of the IgVH somatic mutations in splenic marginal zone lymphoma defines a group of unmutated cases with frequent 7q deletion and adverse clinical course

Cited by 157 publications

References 36 publications

Immunoglobulin VH gene analysis in gastric MALT lymphomas

Immunoglobulin VH gene analysis in gastric MALT lymphomas

Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications

IgV and bcl6 somatic mutation analysis reveals the heterogeneity of cutaneous B-cell lymphoma, and indicates the presence of undisclosed local antigens

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