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-kappaB through enhanced IKK gamma 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.