Radicals accused of causing MALT lymphomas

Cancer in an inflammatory context is an old conundrum. We have accepted the existence of viruses that, in the long run, can cause cancer, and we believe in the association between bilharziosis and cancer of the urinary bladder. It was, however, slightly irritating for many of us to learn that Helicobacter pylori gastritis and an increased rate of gastric malignancies, especially gastric B-cell lymphomas, is not just an epidemiologic association. This ancient, parasitic micro-organism, already dwelling in the stomachs of human infants and, way down the evolutionary tree, of sharks, is indeed a causative agent, as evidenced by lymphoma regression following antibiotic treatment. With researchers extending this fascinating insight into lymphomagenesis, data have been generated by many independent labs converging in the current concept that, in chronic H pylori gastritis, an incremental, initially T-cell-dependent B-cell clonality develops. The first clear-cut evidence that this clonality actually denotes cancer is the emergence of genomic aberrations. In gastric mucosa-associated lymphoid tissue (MALT) lymphomas, at least 3 early genomic events have been described: trisomy 3 (Wotherspoon et al, Blood. 1995; 85:2000-2004) and the translocations t(11; 18)(q21;q21) (Ott et al, Cancer Res. 1997; 57:3944-3948.) and t(1;14)(p22;q32) (Willis et al, Cell. 1999;96:35-45; Zhang et al, Nat Genet. 1999;22:63-68). These 3 structural chromosomal aberrations, although all leading to the histology currently classified as extranodal marginal zone lymphoma (MZL) of MALT could be considered as different diseases. t(11;18)(q21;q21) seems to protect from further malignant progression, as is observed in non-t(11;18)(q21; q21) MZLs of MALT, and may be less sensitive to H pylori eradication. MZLs with t(11;18)(q21;q21) or t(1;14)(p22;q32), although involving differently rearranged genes, may converge in a common pathogenic pathway leading to abnormal activation of NF-κB (Lucas et al, J Biol Chem. 2001;276:19012-19019).

This scenario becomes even more complex against the background of 2 reports published in this issue. Ye and colleagues (page 1012) have found an association between t(11;18)(q21;q21) of gastric MALT lymphomas and CagA strains of H pylori. Furthermore, they show that t(11;18)(q21; q21)-positive MZLs of MALT in other sites do occur, however, in a nonrandom fashion (ie, 38% and 24% in the lung and stomach, respectively, versus 1% in the salivary gland). Ye et al's proposal that the missing link might be chromosomal damage caused by oxidative stress induced by coinfiltrating neutrophils is intriguing. All the more so since this hypothesis is supported by data from Rollinson and colleagues (page 1007). Fascinatingly, using a completely different line of argument, these authors arrive at the very same conclusion. They show that, in their series of gastric MZLs, the glutathione S-transferase GST T1 null genotype and the Interleukin-1 RN2/2 genotype, but not the GST M1 null genotype or Interleukin-1 RN1/1 genotype, are associated with gastric MZLs. Thus, interindividual variations in inflammatory responses and differences in antioxidative capacity may be the genetic background on which H pylori can eventually exert its oncogenic potential. At this stage, it is certainly very important to investigate whether this interindividual variation of inflammatory response might even lead to a specific genetically defined subset of MZLs.