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Negative Gastric MALT Lymphomas Reveal Both Unique and Overlapping Gene Programs

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Negative Gastric MALT Lymphomas Reveal Both Unique and Overlapping Gene Programs Modern Pathology (2010) 23, 458–469 458 & 2010 USCAP, Inc. All rights reserved 0893-3952/10 $32.00 Comparative expressed sequence hybridization studies of t(11;18)(q21;q21)- positive and -negative gastric MALT lymphomas reveal both unique and overlapping gene programs Xavier Sagaert1, Thomas Tousseyn1, Vera Vanhentenrijk1, Peter Van Loo2,3, Mathijs Baens2, Peter Marynen2, Gert De Hertogh1, Karel Geboes1 and Christiane De Wolf-Peeters1 1Section of Morphology and Molecular Pathology, Department of Pathology, Katholieke Universiteit Leuven, Leuven, Belgium; 2Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium and 3Bioinformatics Group, Department of Electrical Engineering (ESAT-SCD), Katholieke Universiteit Leuven, Leuven, Belgium Among the genetic abnormalities reported to occur in MALT lymphomas, the translocation t(11;18)(q21;q21) is of particular interest because it is exclusively documented in MALT lymphomas, mainly with gastrointestinal location. It results in the creation of a fusion protein API2-MALT1 that activates the transcription factor NF-jB through enhanced IKKc polyubiquitination. Here, we apply the recently developed molecular technique termed comparative expressed sequence hybridization to identify differentially expressed chromosomal regions related to the pathogenesis of gastric MALT lymphomas. By comparing t(11;18)(q21;q21)-positive gastric MALT lymphomas to their t(11;18)(q21;q21)-negative counterparts, we found that the location of the MALT1 break point determines a difference in expression pattern within the t(11;18)(q21;q21)-positive group. Moreover, we could define a gastric MALT lymphoma signature, which most likely comprises the regions and genes with significance in the development of MALT lymphomas, by comparing both t(11;18)(q21;q21)-positive and -negative MALT lymphomas to normal lymphoid tissue. Finally, a significant imprint of the marginal zone signature, established by comparing microdissected, splenic B follicles with and without marginal zone, was evident in the expression profile of MALT lymphoma, further supporting a marginal zone origin for this type of B-cell non-Hodgkin’s lymphoma. Modern Pathology (2010) 23, 458–469; doi:10.1038/modpathol.2009.182; published online 15 January 2010 Keywords: CESH; MALT lymphoma; t(11;18)(q21;q21); marginal zone; API2-MALT1 Extranodal marginal zone lymphoma or MALT accounts for approximately 7–8% of all non-Hodg- lymphoma is listed as a separate disease entity in kin’s lymphomas, being the third most frequent the World Health Organization (WHO) classification subtype (after diffuse large B-cell lymphoma and of lymphoid tumors.1 Far from being rare, it follicular lymphoma). Although the stomach is the most common and best-studied site of involvement, MALT lymphomas may be encountered in virtually Correspondence: Dr X Sagaert, MD, PhD, Section of Morphology every organ of the human body. and Molecular Pathology, Department of Pathology, Katholieke Several genetic aberrations in MALT lymphomas Universiteit Leuven, Minderbroederstraat 12, B-3000 Leuven, have been described: aneuploidy, such as trisomy 3 Belgium. and 18,2–4 and chromosomal translocations, such as E-mail: [email protected] Received 21 September 2009; revised and accepted 9 December t(1;14)(p22;q32), t(14;18)(q32;q21), t(3;14)(3p13;q32) 5–13 2009; published online 15 January 2010 and t(11;18)(q21;q21). The latter genetic anomaly www.modernpathology.org Gene expression patterns in gastric MALT lymphomas X Sagaert et al 459 was first described in 198914 and is the most In this study, we aimed to get more insight into the common translocation in MALT lymphomas. It pathogenesis of gastric MALT lymphomas in general leads to the generation of a fusion protein compris- and to study the impact of the API2-MALT1 fusion ing the three baculovirus inhibitor of apoptosis protein. To this end, we compared t(11;18)(q21;q21)- protein repeat domains present in the N terminus positive and -negative gastric MALT lymphomas of the API2 protein (encoded by the API2 gene with each other and with normal spleen by CESH located on chromosome 11) and a variable part of expression profiling. In addition, we evaluated the MALT1 protein (encoded by the MALT1 gene similarities and differences between the gastric located on chromosome 18), which always contains MALT lymphoma expression profile and the mar- the caspase p20-like domain.6 This API2-MALT1 ginal zone expression signature. The latter was fusion protein can activate NF-kB in vitro, affecting established using CESH analysis, comparing laser- a number of survival-related genes.15 A high in- microdissected B follicles with and without margin- cidence of the t(11;18)(q21;q21) is observed in al zone, taken from normal spleen biopsies. MALT-type lymphomas with a gastric and to a lesser extend pulmonary location (ranging from 10 to 50%), whereas this translocation is almost never Materials and methods found in MALT lymphomas of other extranodal Tissue Samples tissues.7,8,16–19 The presence of the API2-MALT1 fusion transcript has been linked to resistance of the Fourteen primary gastric MALT lymphomas were gastric MALT lymphoma to Helicobacter pylori retrieved from the archives of the Department of eradication and to the absence of transformation to Pathology (University Hospital, Katholieke Univer- a more aggressive large B-cell lymphoma.5,20,21 siteit Leuven, Leuven, Belgium). For each case, Moreover, the t(11;18)(q21;q21) has not been de- freshly frozen tumor tissue and formalin-fixed scribed in other B-cell lymphomas and its presence paraffin-embedded blocks were available. These in MALT lymphomas apparently excludes any cases were diagnosed in our department between further chromosomal aberrations.22 1987 and 1997 according to the Revised European– To investigate the molecular mechanisms under- American Lymphoma classification and the WHO lying the pathogenetic role of t(11;18)(q21;q21) in criteria. They were composed of a monotonous MALT lymphomas, we applied a recently developed proliferation of small centrocyte-like cells (with no molecular cytogenetic technique termed compara- or minimal variation in shape and size) mixed up tive expressed sequence hybridization (CESH).23 with a very small number of lymphocyte-like This technique gives a genome-wide view of relative cells and a few large activated B cells; residual expression patterns within tissues according to reactive follicle centers were present in most cases. chromosomal location in a way similar to that of Ten of these cases showed the t(11;18)(q21;q21), comparative genomic hybridization (CGH). This is whereas the remaining four cases were achieved by converting RNA extracted from the t(11;18)(q21;q21) negative; the presence or absence test sample into cDNA, amplifying it by PCR and of t(11;18)(q21;q21) was determined by RT–PCR in a competitively hybridizing this to normal metaphase previously published study.5 In all 10 positive cases, chromosomes in the presence of cDNA obtained the break points within the API2 gene occurred from a reference tissue. The cDNAs from the test consistently in intron 7 (annotated now as intron 6 sample and the reference tissue are labeled with according to Ensembl gene ENSG00000023445) different fluorochromes, and the ratio of the whereas the break points within the MALT1 coding fluorescence intensities of these two fluorochromes DNA were variable and located in intron 4 (4 cases), (measured as in CGH) is considered to represent 7 (4 cases) and 8 (2 cases), resulting respectively in differential gene expression. Although CESH an API2/exon7-MALT1/exon5, API2/exon7-MALT1/ has a lower resolution in comparison to microarrays, exon8 and API2/exon7-MALT1/exon9 fusion. The it requires only a minimal amount of material detailed clinical and genetic data of all cases are and because of the use of a chromosomal provided in Table 1. In addition, snap-frozen spread neither the number nor the sequence of the biopsies of six splenectomy specimens (with a genes as applied on a microarray target slide prominent marginal zone but without obvious is of importance. It is especially well suitable in morphologic anomalies) of healthy individuals circumstances where the number of informative having traumatic rupture of the spleen were selected biopsies is small. We previously applied this new and used as reference tissues in a series of CESH technique with success to the study of hairy cell experiments to study the signature of MALT lym- leukemia and breast tumors; the established phoma vs nonneoplastic tissue as well as to study profiles allowed us to identify a possible the signature of the marginal zone. For CESH marginal zone origin of hairy cell leukemia and to analysis, frozen tissue blocks were used, which distinguish particular subgroups of breast tu- had been stored at À801C immediately after surgical mors.24,25 Other groups successfully used CESH in excision. All frozen MALT lymphoma samples the study of solid tumors and childhood acute consisted of tumor for more than 60% when lymphoblastic leukemia.23,26,27 evaluated by hematoxylin/eosin staining. Modern Pathology (2010) 23, 458–469 Gene expression patterns in gastric MALT lymphomas 460 X Sagaert et al This study was approved by the institutional ethics commission of the Katholieke Universiteit Leuven. Informed consent was provided according to the Declaration of Helsinki Principles. Helicobacter pylori RNA Isolation and Reverse Transcription (18q21) genes, as previously Total RNA was extracted from eight to ten 20 mm sections of each frozen tissue block, using the MALT1 related to chronic Rneasy Mini Kit (Qiagen, Venlo, the Netherlands) following the manufacturer’s recommendations. RNA quality/integrity was controlled by agarose gel electrophoresis (1%) and its concentration was ; NA, not available. (14q32) and measured using a nanodrop spectrophotometer (Nanodrop Technologies, Wilmington, DE, USA). IGH RNA (25 mg) was treated with 2 U RNase-free DNase (Promega, Leiden, the Netherlands) during 45 min Follow-up CR after secondary treatment PR and SD after recurrent therapy (surg, RT, CT, Hp eradication) (11q21), and further purified using phenol–chloroform.
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