The Product of the t(11;18), an API2-MLT Fusion, Marks Nearly Half of Gastric MALT Type Lymphomas without Large Cell Proliferation

Abstract

Recently we demonstrated that the t(11;18)(q21;q21) associated with extranodal marginal zone B cell lymphomas of MALT type results in the expression of a chimeric transcript fusing 5 API2 on chromosome 11 to 3 MLT on chromosome 18. Here we report the development of an RT-PCR approach for the detection of the API2-MLT fusion transcript and its application for the analysis of 58 cases of gastric lymphoma. Initially nested PCR amplification was combined with Southern analysis using internal API2 and MLT probes. A genuine API2-MLT fusion transcript of variable length was demonstrated in 11 out of 58 cases. Sequence analysis revealed that in all cases the breakpoint on chromosome 11 occurred between exons 7 and 8 of the API2 gene. In contrast, the breakpoints on chromosome 18 appeared to be heterogeneous as fusions to bp 814, 1123, and 1150, respectively, of MLT were observed. These observations allowed us to work out a highly sensitive diagnostic test for the API2-MLT fusion on an ABI Prism 7700 sequence detector that confirmed the results of our initial approach. The API2-MLT fusion was found in 48% of gastric marginal zone cell lymphomas of MALT type that did not contain a large cell component and it was lacking in all other lymphomas of the stomach.

t(11;18)(q21;q21) in extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue in stomach: a study of 48 cases

“…The t(11;18)(q21;q21) translocation has been associated with 24-48% of gastric MZL-MALT. 8,[12][13][14][15] The gastric MZL-MALTs with t(11;18)(q21;q21) and a subset of MZL-MALT with large cell change have been shown to be resistant to treatment for H. pylori eradication. Otherwise eradication of H. pylori will lead to complete regression in about 70% of gastric MZL-MALT.…”

Comparative expressed sequence hybridization studies of t(11;18)(q21;q21)-positive and -negative gastric MALT lymphomas reveal both unique and overlapping gene programs

“…Ten of these cases showed the t(11;18)(q21;q21), whereas the remaining four cases were t(11;18)(q21;q21) negative; the presence or absence of t(11;18)(q21;q21) was determined by RT-PCR in a previously published study. 5 In all 10 positive cases, the break points within the API2 gene occurred consistently in intron 7 (annotated now as intron 6 according to Ensembl gene ENSG00000023445) whereas the break points within the MALT1 coding DNA were variable and located in intron 4 (4 cases), 7 (4 cases) and 8 (2 cases), resulting respectively in an API2/exon7-MALT1/exon5, API2/exon7-MALT1/ exon8 and API2/exon7-MALT1/exon9 fusion. The detailed clinical and genetic data of all cases are provided in Table 1.…”

“…7,8,[16][17][18][19] The presence of the API2-MALT1 fusion transcript has been linked to resistance of the gastric MALT lymphoma to Helicobacter pylori eradication and to the absence of transformation to a more aggressive large B-cell lymphoma. 5,20,21 Moreover, the t(11;18)(q21;q21) has not been described in other B-cell lymphomas and its presence in MALT lymphomas apparently excludes any further chromosomal aberrations. 22 To investigate the molecular mechanisms underlying the pathogenetic role of t(11;18)(q21;q21) in MALT lymphomas, we applied a recently developed molecular cytogenetic technique termed comparative expressed sequence hybridization (CESH).…”

“…[5][6][7][8][9][10][11][12][13] The latter genetic anomaly was first described in 1989 14 and is the most common translocation in MALT lymphomas. It leads to the generation of a fusion protein comprising the three baculovirus inhibitor of apoptosis protein repeat domains present in the N terminus of the API2 protein (encoded by the API2 gene located on chromosome 11) and a variable part of the MALT1 protein (encoded by the MALT1 gene located on chromosome 18), which always contains the caspase p20-like domain.…”

p16/INK4a gene methylation is a frequent finding in pulmonary MALT lymphomas at diagnosis

“…2,3 Since this fusion is often the sole gene abnormality found in MALT lymphoma and has not been found in other types of lymphoma, API2-MALT1 fusion has been considered as a specific MALT lymphoma-causing alteration. [4][5][6] API2 is a member of the IAP (inhibitor of apoptosis) gene family, and is essential for the suppression of apoptosis. 7 MALT1 is identical to a novel caspase-like protein termed paracaspase, 8 although its biologic function remains unclear.…”