Significant association between <i>TNFAIP3</i> inactivation and biased immunoglobulin heavy chain variable region 4‐34 usage in mucosa‐associated lymphoid tissue lymphoma

Moody, Sarah; Escudero‐Ibarz, Leire; Wang, Ming; Clipson, Alexandra; Ochoa, Eguzkine; Dunn‐Walters, Deborah K.; Xue, Xuemin; Zeng, Naiyan; Robson, Alistair; Chuang, Shih‐Sung; Cogliatti, Sergio; Liu, Hongxiang; Goodlad, John R.; Ashton‐Key, Margaret; Raderer, Markus; Bi, Yingwen; Du, Ming‐Qing

doi:10.1002/path.4933

Cited by 27 publications

(43 citation statements)

References 22 publications

(43 reference statements)

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“…Helicobacter pylori status in gastric ENMZL cases was not available due to the retrospective nature of the study. Overall, these findings confirm and significantly extend previous observations about the existence of Ig gene repertoire biases in MZ lymphomas .…”

Section: Resultssupporting

confidence: 91%

Disease‐biased and shared characteristics of the immunoglobulin gene repertoires in marginal zone B cell lymphoproliferations

Xochelli

Bikos

Polychronidou

et al. 2019

The Journal of Pathology

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The B cell receptor immunoglobulin (Ig) gene repertoires of marginal zone (MZ) lymphoproliferations were analyzed in order to obtain insight into their ontogenetic relationships. Our cohort included cases with MZ lymphomas (n = 488), i.e. splenic (SMZL), nodal (NMZL) and extranodal (ENMZL), as well as provisional entities (n = 76), according to the WHO classification. The most striking Ig gene repertoire skewing was observed in SMZL. However, restrictions were also identified in all other MZ lymphomas studied, particularly ENMZL, with significantly different Ig gene distributions depending on the primary site of involvement. Cross‐entity comparisons of the MZ Ig sequence dataset with a large dataset of Ig sequences (MZ‐related or not; n = 65 837) revealed four major clusters of cases sharing homologous (‘public’) heavy variable complementarity‐determining region 3. These clusters included rearrangements from SMZL, ENMZL (gastric, salivary gland, ocular adnexa), chronic lymphocytic leukemia, but also rheumatoid factors and non‐malignant splenic MZ cells. In conclusion, different MZ lymphomas display biased immunogenetic signatures indicating distinct antigen exposure histories. The existence of rare public stereotypes raises the intriguing possibility that common, pathogen‐triggered, immune‐mediated mechanisms may result in diverse B lymphoproliferations due to targeting versatile progenitor B cells and/or operating in particular microenvironments. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Resultssupporting

confidence: 91%

Disease‐biased and shared characteristics of the immunoglobulin gene repertoires in marginal zone B cell lymphoproliferations

Xochelli

Bikos

Polychronidou

et al. 2019

The Journal of Pathology

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“…[66][67][68][69] This recalls previous observations of biased associations of specific BCR IGHV genes and particular genomic alterations in other B-cell lymphomas, including enrichment of mutations involving SF3B1 in CLL subset 2, 70 MAP2K1 in IGHV4-34 hairy cell leukemia, 71 KLF2 in IGHV1-2*04 splenic marginal zone lymphoma, 72 and TNFAIP3 in IGHV4-34 ocular adnexa marginal zone lymphoma. 73 This may reflect an exquisite synergy of immunogenic and oncogenic driving forces underlying tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Primary vitreoretinal lymphomas display a remarkably restricted immunoglobulin gene repertoire

et al. 2020

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Primary vitreoretinal lymphoma (PVRL) is a high-grade lymphoma affecting the vitreous and/or the retina. The vast majority of cases are histopathologically classified as diffuse large B-cell lymphoma (DLBCL) and considered a subtype of primary central nervous system lymphoma (PCNSL). To obtain more insight into the ontogenetic relationship between PVRL and PCNSL, we adopted an immunogenetic perspective and explored the respective immunoglobulin gene repertoire profiles from 55 PVRL cases and 48 PCNSL cases. In addition, considering that both entities are predominantly related to activated B-cell (ABC) DLBCL, we compared their repertoire with that of publicly available 262 immunoglobulin heavy variable domain gene rearrangement sequences from systemic ABC-type DLBCLs. PVRL displayed a strikingly biased repertoire, with the IGHV4-34 gene being used in 63.6% of cases, which was significantly higher than in PCNSL (34.7%) or in DLBCL (30.2%). Further repertoire bias was evident by (1) restricted associations of IGHV4-34 expressing heavy chains, with κ light chains utilizing the IGKV3-20/IGKJ1 gene pair, including 5 cases with quasi-identical sequences, and (2) the presence of a subset of stereotyped IGHV3-7 rearrangements. All PVRL IGHV sequences were highly mutated, with evidence of antigen selection and ongoing mutations. Finally, half of PVRL and PCNSL cases carried the MYD88 L265P mutation, which was present in all 4 PVRL cases with stereotyped IGHV3-7 rearrangements. In conclusion, the massive bias in the immunoglobulin gene repertoire of PVRL delineates it from PCNSL and points to antigen selection as a major driving force in their development.

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“…The patient with orbital lymphoma had the recently noted association of a TNFAIP3 mutation and IGHV4-34 usage in this subset of MZL. 18 Three patients had repeat genomic analysis at evolution, and no new mutations were found.…”

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confidence: 97%

CBL-MZ is not a single biological entity: evidence from genomic analysis and prolonged clinical follow-up

et al. 2018

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The term "clonal B cell lymphocytosis of marginal zone origin" (CBL-MZ) 1,2 has recently been suggested for asymptomatic individuals whose routine blood count shows a persistent modest lymphocytosis that is usually accompanied by bone marrow involvement. This immunophenotype is suggestive of marginal zone/postgerminal center derivation, but no other features of a chronic B cell lymphoproliferative disorder are found, other than a low-level paraprotein in some cases. Cases with a clonal lymphocyte count ,5 3 10 9 /L would fall within the revised World Health Organization (WHO) category of non-chronic lymphocytic leukemia-type monoclonal B-cell lymphocytosis. In 3 previous series of CBL-MZ consisting of 102, 53, and 16 cases with median follow-ups (FUs) of 60, 34, and 44 months, respectively, 1,3,4 the overall incidence of progression was 15.7%, with the majority (11.1%) developing splenomegaly that frequently did not require treatment. However, it remains unclear whether CBL-MZ is the precursor to 1 or several well-defined WHO entities and what factors predict disease progression. To address this, we performed a genomic analysis of a well-characterized cohort of CBL-MZ cases with long FU and provide evidence to show that CBL-MZ is not a single biological entity.This study includes data from 37 patients with CBL-MZ diagnosed and managed at the Royal Bournemouth Hospital. Clinical, routine laboratory, morphological, immunophenotypic, immunogenetic, and cytogenetic data have been reported on 36 cases using previously described methods.

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Significant association between TNFAIP3 inactivation and biased immunoglobulin heavy chain variable region 4‐34 usage in mucosa‐associated lymphoid tissue lymphoma

Cited by 27 publications

References 22 publications

Disease‐biased and shared characteristics of the immunoglobulin gene repertoires in marginal zone B cell lymphoproliferations

Disease‐biased and shared characteristics of the immunoglobulin gene repertoires in marginal zone B cell lymphoproliferations

Primary vitreoretinal lymphomas display a remarkably restricted immunoglobulin gene repertoire

CBL-MZ is not a single biological entity: evidence from genomic analysis and prolonged clinical follow-up

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