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Sagaert X et al . VH gene mutation status in gastrointestinal MALT lymphomas indicates that nodal marginal zone lymphomas and MALT lymphomas, occurring at different anatomic sites and either with or without the t(11;18)(q21;q21), may be derived from B cells that are driven by similar antigen epitopes. Moreover, Marasca et al. observed an association between the use of the VH1-69 gene in a series of nodal marginal zone lymphomas and the occurrence of Hepatitis C virus infection. Unfortunately, the Hepatitis C virus infection status of our 2 cases using VH1-69 gene was not known. In view of the reported association between CD27 expression in B cells and the presence of somatic hypermutations, we stained all 7 MALT lymphomas for CD27 and correlated these immunohistochemical data with the VH gene mutation status. No specific correlation between CD27 expression and the mutation status of the VH gene was found, as strong CD27 expression did occur in the one case (case 6) with an intact germline VH gene, while there was a lack of CD27 expression in the one case (case 1) that displayed the second most diversified VH gene. This observation is in line with data on mice models that questioned whether CD27 is a marker of memory B cells, since CD27 expression did occur in somatically unmutated B cells and CD27 deficiency did not affect somatic diversification in a CD27 knockout mice model [58] . As such, our study does not support the hypothesis that CD27 is a general marker of somatically mutated B cells and further emphasises that the only definitive marker of memory B cells thus far identified is the presence of somatically mutated immunoglobulins. However, our data on CD27 expression should be interpreted with caution as the precise role of (loss of) CD27 expression in (marginal zone) lymphomas remains to be investigated. Apart from the evidence for antigen selection of the lymphomatous cells, others have found that ongoing mutation (i.e. intraclonal variation) of the VH genes indicating that continuing antigen stimulation may play a role in the clonal expansion of the MALT lymphoma B cells [30,32,34,35,38] . Our approach using direct sequencing of DNA extracted from whole tissue sections does not allow the identification of subclones within a lymphomatous proliferation. Nevertheless, from case 6, we were able to analyse DNA from the diagnostic sample as well as DNA from a gastric biopsy taken 54 months later. Case 6 was a t(11;18)(q21;q21)positive MALT lymphoma diagnosed with large masses in the upper intestine, extending into the stomach. This patient showed evidence of minimal residual disease at all time points of his follow-up, as shown by the detection of the API2-MALT1 fusion transcripts and of the reciprocal genomic fusion. The latter is confirmed by the results of the present study, demonstrating the presence of lymphoma cells in the stomach harbouring the same VDJ rearrangement as used by the initial intestinal lymphoma cells, 4.5 years after the original diagnosis. Moreover, the VH gene was unmutated in both samples. The lack of VH somatic mutations in the diagnostic as well as in the follow-up sample, indicates that this t(11;18)(q21;q21)-positive MALT lymphoma is composed of naive B cells that have not yet gone through the germinal centre reaction and, therefore, tumor growth seems not to be stimulated by a T cell dependent antigen response. As shown in Table 1, this case was characterised by relapse in the stomach after one year, with stable disease thereafter (despite intensive therapy). Remarkably, in some B cell non-Hodgkin lymphomas, the lack of somatic mutations has been linked to an unfavourable clinical outcome. As such, patients with chronic lymphocytic leukaemia or mantle cell lymphoma whose tumors have mutated VH genes have a better prognosis than those with intact germline VH genes [59-61] . As all cases analysed in this study showed the presence of the t(11;18)(q21;q21), we may speculate on the stage of B cell differentiation at which this genetic abnormality is acquired. Several possibilities can be considered. Firstly, our results may indicate that the t(11;18)(q21;q21) can be acquired at different stages of B cell differentiation.However, the hypothesis that the t(11;18)(q21;q21) may confer a transforming potential to the preceding antigen mediated lymphoid proliferation, is supported only by some of the cases, i.e. those with mutated VH genes and evidence of antigen selection. Secondly, it may be hypothesised that the acquisition of the t(11;18)(q21;q21) occurs at a naive B cell stage in all cases, representing the primary proliferation stimulus, and that somatic VH mutations are acquired after the malignant transformation induced by the API2-MALT1 fusion transcript. An additional pathogenic role of antigen stimulation at the origin and/or expansion of the lymphoma, acting synergistic with the API2-MLT fusion protein cannot be excluded. The evidence for (auto-)antigen selection that we found in some of the cases may be supportive of this latter suggestion. However, this hypothesis seems to conflict with the fact that H. pylori reactive T-cells have been shown to drive gastric MALT lymphoma cells, regardless of the presence or absence of the t(11;18)(q21;q21) [62] . Alternatively, the acquisition of somatic VH mutations in an t(11;18)(q21;q21)-positive MALT lymphoma might represent an epiphenomenon without important significance. ACKNOWLEDGMENTS The authors thank Miet Vanherck for excellent technical assistance. COMMENTS Background MALT lymphomas are tumors that arise from the marginal zone compartment of the B-follicle at extranodal sites. Gastric MALT lymphoma accounts for 5% of all gastric neoplasia and at least 50% of all gastric lymphomas, making it the most frequent lymphoma of the gastrointestinal tract. Its pathogenesis is clearly linked with Helicobacter pylori (H. pylori) gastritis and 25% of all gastric MALT lymphomas display the translocation t(11;18)(q21;q21). Research frontiers The t(11;18)(q21;q21) results in the expression of the aberrant API2-MALT1 fusion protein. Presence of API2-MALT1 in gastric MALT lymphomas is associated with resistance to H. pylori eradication therapy and with the absence of any further genetic instability or chromosomal imbalances. In this study, the authors investigate how t(11;18)(q21;q21)-positive gastrointestinal MALT lymphomas relate to other marginal zone lymphomas with respect to the somatic mutation pattern of the VH genes and the expression of the marker CD27. Innovations and breakthroughs Reports show that both gastric and non-gastric MALT lymphomas harbour unmutated, slightly or highly mutated VH genes, indicating that they are composed either of naive B cells or of early or late memory B cells. This is the first study analysing the VH mutation status in a series of gastrointestinal MALT lymphomas in correlation with the t(11;18)(q21;q21). It was found that the presence or absence of the WJGO|www.wjgnet.com 30 February 15, 2011|Volume 3|Issue 2|
API2-MALT1 fusion transcript is not related to a particular B cell stage from which the MALT lymphoma originates. In addition, we provide evidence that CD27 is not a marker of somatically mutated B-cells, contrary to what is generally believed. Applications By understanding at what B-cell stage the t(11;18)(q21;q21) is acquired, this study may contribute to a better understanding of the pathogenesis of gastrointestinal MALT lymphomas in general and may be of importance to therapeutic strategies that target the API2-MALT1 fusion transcript and/or interfere with the NF-kB pathway. Terminology API2 and MALT1 are proteins that play a key role in the antigen receptor-mediated activation of NF-kB, which is the transcription factor of a number of survival- and proliferation-related genes in B cells. Not surprisingly, the formation of an aberrant fusion protein API2-MALT1 will deregulate the NF-kB pathway and result in uncontrolled B-cell proliferation and thus (gastrointestinal MALT) lymphomagenesis. Peer review In this work, the author reported the association between the VH gene mutation and T(11;18)(q21;q21)-positive gastric MALT lymphomas. And they suggest that this translocation will target different stage of B-cells. Their observation is interesting, however, the clinical sample size is somewhat small. REFERENCES 1 Jaffe ES, Harris N, Stein H, Vardiman J. World Health Organisation Classification of Tumours: Pathology and Genetics: Tumours of Haemopoietic and Lymphoid Tissues. Lyon, France: IAR Press; 2008 2 Suarez F, Lortholary O, Hermine O, Lecuit M. Infectionassociated lymphomas derived from marginal zone B cells: a model of antigen-driven lymphoproliferation. Blood 2006; 107: 3034-3044 3 Baens M, Maes B, Steyls A, Geboes K, Marynen P, De Wolf- Peeters C. The product of the t(11;18), an API2-MLT fusion, marks nearly half of gastric MALT type lymphomas without large cell proliferation. Am J Pathol 2000; 156: 1433-1439 4 Streubel B, Lamprecht A, Dierlamm J, Cerroni L, Stolte M, Ott G, Raderer M, Chott A. T(14;18)(q32;q21) involving IGH and MALT1 is a frequent chromosomal aberration in MALT lymphoma. Blood 2003; 101: 2335-2339 5 Wlodarska I, Veyt E, De Paepe P, Vandenberghe P, Nooijen P, Theate I, Michaux L, Sagaert X, Marynen P, Hagemeijer A, De Wolf-Peeters C. FOXP1, a gene highly expressed in a subset of diffuse large B-cell lymphoma, is recurrently targeted by genomic aberrations. Leukemia 2005; 19: 1299-1305 6 Ruland J, Duncan GS, Wakeham A, Mak TW. Differential requirement for Malt1 in T and B cell antigen receptor signaling. Immunity 2003; 19: 749-758 7 Ruefli-Brasse AA, French DM, Dixit VM. Regulation of NFkappaB-dependent lymphocyte activation and development by paracaspase. Science 2003; 302: 1581-1584 8 Isaacson PG, Du MQ. 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Clonal evolution of a follicular lymphoma: evidence for antigen selection. Proc Natl Acad Sci USA 1992; 89: 6770-6774 24 Hummel M, Tamaru J, Kalvelage B, Stein H. Mantle cell (previously centrocytic) lymphomas express VH genes with no or very little somatic mutations like the physiologic cells of the follicle mantle. Blood 1994; 84: 403-407 25 Algara P, Mateo MS, Sanchez-Beato M, Mollejo M, Navas IC, Romero L, Solé F, Salido M, Florensa L, Martínez P, Campo E, Piris MA. Analysis of the IgV(H) somatic mutations in splenic marginal zone lymphoma defines a group of unmutated cases with frequent 7q deletion and adverse clinical course. Blood 2002; 99: 1299-1304 26 Bahler DW, Miklos JA, Swerdlow SH. Ongoing Ig gene hypermutation in salivary gland mucosa-associated lymphoid tissue-type lymphomas. Blood 1997; 89: 3335-3344 27 Bahler DW, Kim BK, Gao A, Swerdlow SH. Analysis of immunoglobulin V genes suggests cutaneous marginal zone B-cell lymphomas recognise similar antigens. Br J Haematol 2006; 132: 571-575 28 Camacho FI, Algara P, Mollejo M, García JF, Montalbán C, Martínez N, Sánchez-Beato M, Piris MA. Nodal marginal zone lymphoma: a heterogeneous tumor: a comprehensive analysis of a series of 27 cases. Am J Surg Pathol 2003; 27: 762-771 29 Conconi A, Bertoni F, Pedrinis E, Motta T, Roggero E, Luminari S, Capella C, Bonato M, Cavalli F, Zucca E. Nodal mar- WJGO|www.wjgnet.com 31 February 15, 2011|Volume 3|Issue 2|
Page 1 and 2: World Journal of Gastrointestinal O
Page 3: Guo-Qiang Xu, Hangzhou Winnie Yeo,
Page 6 and 7: Contents ACKNOWLEDGMENTS APPENDIX A
Page 8 and 9: Freeman HJ et al . Intestinal lymph
Page 10 and 11: Freeman HJ et al . Intestinal lymph
Page 12 and 13: Online Submissions: http://www.wjgn
Page 15 and 16: A Table 3 Primer sequences Primer S
Page 17: gastrointestinal MALT lymphomas is
Page 25 and 26: Author contributions: The format of
Page 27: Examples for paper writing Editoria

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