Genetic Characterization and Clinical Features of Helicobacter pylori Negative Gastric Mucosa-Associated Lymphoid Tissue Lymphoma

SIMPLE SUMMARY: The pathogenesis of H. pylori-associated gastric MALT lymphoma has been well characterized, but the genetic basis and clinical features of H. pylori negative gastric cases remain elusive. In the present study, we investigated the genetic profiles of a large series of H. pylori negative gastric MALT lymphoma by targeted sequencing for a panel of genes specifically designed for marginal zone lymphoma, together with assessment of common translocations and comprehensive clinical data. Targeted sequencing confirmed that NF-κB activation is a major driver in the pathogenesis of H. pylori negative MALT lymphoma, as shown by frequent TNFAIP3 inactivating mutations and also by translocations of MALT1/IGH. This study adds new insights into the genetic background of H. pylori negative MALT lymphoma and will potentially allow us to more specifically target the underlying molecular pathways in future therapeutic concepts. ABSTRACT: Background: In Western countries, the prevalence of gastric mucosa-associated lymphoid tissue (MALT) lymphoma has declined over the last three decades. Contemporaneously, H. pylori negative gastric MALT lymphoma is increasingly encountered, and their genetic basis and clinical features remain elusive. Methods: A total of 57 cases of H. pylori negative gastric MALT lymphoma were reviewed and investigated for chromosome translocation by fluorescence in-situ hybridization and for somatic mutations by the targeted sequencing of 93 genes. Results: MALT1 translocation, most likely t(11;18)(q21;q21)/BIRC3-MALT1, was detected in 39% (22/57) cases, and IGH translocation was further seen in 12 MALT1-negative cases, together accounting for 60% of the cohort. Targeted sequencing was successful in 35 cases, and showed frequent mutations in NF-κB signaling pathways (TNFAIP3 = 23%, CARD11 = 9%, MAP3K14 = 9%), together affecting 14 cases (40%). The NF-κB pathway mutations were mutually exclusive from MALT1, albeit not IGH translocation, altogether occurring in 86% of cases. There was no significant correlation between the genetic changes and clinicopathological parameters. The patients showed a median of progression-free survival (PFS) of 66.3 months, and a significant superior PFS when treated with systemic versus antibiotic therapy (p = 0.004). Conclusion: H. pylori negative gastric MALT lymphoma is characterized by highly frequent genetic changes in the NF-κB signaling pathways.