Immunoglobulin VH gene analysis in gastric MALT lymphomas

Abstract

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

Early-Stage Gastric MALT Lymphoma: Is It a Truly Localized Disease?

“…Another interesting finding was the more frequent usage of the VH3 gene family by blood and gastric clones. A similar finding was recently reported by Sakuma et al [49], who analyzed VH gene usage in gastric biopsies of GML patients. They found that the most frequently used genes belonged to the VH3 gene family and specifically VH3-23 and VH3-30.…”

Defective Stromal Remodeling and Neutrophil Extracellular Traps in Lymphoid Tissues Favor the Transition from Autoimmunity to Lymphoma

“…Prototypical examples of such an association include mucosa-associated lymphoid tissue (MALT) lymphomas of the salivary glands and enteropathy-associated T-cell lymphomas arising in patients with Sjogren's syndrome or celiac disease, respectively ( 2,3 ). Malignant lymphoid clones of the ocular adnexa and gastric MALT lymphomas associated with Chlamydophila psittaci and Helicobacter pylori infection, respectively, frequently express immunoglobulin V H genes that are typically found in rheumatoid arthritis, systemic lupus erythematous (SLE), and other autoimmune disorders (4)(5)(6). Moreover, signs of lymphoid clone selection driven by autoantigens can be recognized in the B-cell receptor (BCR) confi guration of chronic lymphocytic leukemia (CLL), splenic marginal zone lymphoma (MZL), and mantle cell lymphoma (MCL), none of which has been causally related to any specifi c infective, infl ammatory, or autoimmune disease (7)(8)(9).…”

1086 IGHV1-69 as a Promising Candidate for the Development of a Shared Immunotherapy to B-cell Lymphomas

“…Available data clearly indicate that IGHV1-69 is characterized by both tumor specificity issues and a shared expression among different B-NHL [28,30,[57][58][59][60][61]71,77,81], thus combining the advantages of a reduced toxicity due to limited side effects, and decreased times and costs of production if compared to patient-tailored vaccines. In order to emphasize the properties of shared antigen, we designed an optimized IGHV1-69 sequence, conceived to enhance its similarity degree in respect to several IGHV1-69 sequences, obtained not only from different patients, but also in the context of various malignancies, while preserving or even enhancing immunogenicity.…”

“…Gastric MALT inflammation-dependent tumors frequently used V H 3-23 and V H 3-30 fragments, which have been closely associated also with autoimmune diseases. Indeed, they have been frequently used in thymic MALT lymphoma, a tumor closely associated with autoimmune disease [59]; while salivary MALT lymphomas B-cells mainly express V H 1-69 [60].…”

“…Gastric MALT inflammation-dependent tumors frequently used V H 3-23 and V H 3-30 fragments, which have been closely associated also with autoimmune diseases. Indeed, they have been frequently used in thymic MALT lymphoma, a tumor closely associated with autoimmune disease [59]; while salivary MALT lymphomas B-cells mainly express V H 1-69 [60].Some papers revealed also the shared use of a specific Ig rearrangement in different lymphoma histotypes, as for example the expression of V H 4-34 frequently found in diffuse large-cell lymphoma, primary central nervous system lymphoma, B-chronic lymphocytic leukemia (CLL), and autoimmune disorders, and expressed in about 5% of healthy adult B lymphocytes [61].In CLL, the mutational status of the immunoglobulin genes expressed in tumor B-cells can be used to segregate patients into 2 subsets that have significantly different rates of disease progression: the unmutated VH genes are associated with a greater tendency for disease progression and shorter survival than the mutated ones. Within the unmutated group several studies revealed that the Ig repertoire shows a reduce variability compared with that of adult blood B cells, with a frequent use of V H 1-69, V H 3-07, V H 3-21, and V H 4-34, and a skewed D3-3 and J6 gene usage with restricted reading frames (RFs) in particularly linked to the V H 1-69 expression [30,31].…”