Molecular Phenotype Distinguishes Two Subsets of Gastric Low-Grade Mucosa-Associated Lymphoid Tissue Lymphomas

Abstract

Isotype switch recombination together with somatic mutation of immunoglobulin variable genes is indicative of B-cell maturation stage. Because aberrant isotype switch events occur in a proportion of gastric mucosa-associated lymphoid tissue (MALT) lymphomas, we tested whether gastric MALT lymphomas with or without aberrant rearrangements in the switch regions differ in B-cell maturation stage. Southern blot analysis of DNA from six gastric MALT lymphoma cases revealed the presence of aberrant isotype switch events in three cases. Somatic common mutations were present in all immunoglobulin variable heavy chain genes of the six cases, and homology with the closest germline ranged from 89.5% to 98.8%. Replacement versus silent mutation ratio analysis of complementarity-determining regions and frameworks indicated the positive selective pressure of an antigen in four cases. In the remaining two cases, protein translated from the third complementarity-determining region suggested the selective pressure of an autoantigen. The three cases with aberrant isotype switch events showed no noncommon mutations, whereas two of three cases without evidence of aberrant isotype switch showed high levels of such mutations. Moreover the three cases with aberrant isotype switch, compared with the three cases without, showed an increased number of common mutations and of N segment additions. These data raise the possibility of two distinct subsets of gastric low-grade MALT lymphomas, one with aberrant isotype switch and no intraclonal diversification, and one with no aberrant isotype switch but with intraclonal diversification. The first subset may originate from a postgerminal center environment and the second from a germinal center. Alternatively, the first subset may derive from the second after maturation or after a transformation event that blocks the mutational process.