Characterization of genetic events involving IgH switch regions in gastric low-grade MALT lymphomas and B-CLL

Nardini, Elena (2002). Characterization of genetic events involving IgH switch regions in gastric low-grade MALT lymphomas and B-CLL. PhD thesis The Open University.



This thesis adresses immunoglobulin heavy chain switch regions and variable regions in two hematologic B-cell tumors, mucosa-associated lymphoid tissue (MALT) lymphoma and B-cell chronic lymphocytic leukemia (B-CLL).

A high proportion of IgM+ MALT lymphoma cases were found to bear genetic alterations in the switch regions. Most of these switch region genetic alterations have been characterized through molecular cloning as chromosomal insertions and internal deletions but no new gene has been identified. Variable regions analysis revealed the presence of somatic hypermutations in all cases and intraclonal variation in a proportion of these. Correlation of somatic hypermutations and intraclonal variation with switch region alterations raised the possibility of two distinct subsets of MALT lymphoma with different maturation: one subset with aberrant isotype switch and no intraclonal diversification, and the other one with no aberrant isotype switch but with intraclonal diversification. Replacement versus silent mutation ratio analysis of complementarity-determining regions and frameworks indicated the positive selective pressure of an antigen in most cases. In two cases, protein translated from the third complementarity-determining region suggested the selective pressure of an autoantigen. A correlation of switch region alterations with clinical behaviour revealed that cases with rearrangements have a longer disease-free time after gastrectomy.

In B-CLL switch region analysis demonstrated the presence of switch region alterations in a proportion of cases (34%). These alterations are in most cases internal deletions of the switch mu region and their role remains to be determined although their localization in the VhDJh rearranged alleles suggests a role in the stabilization of the isotype of the expressed immunoglobulin. Variable regions analysis showed somatic hypermutations in a proportion of cases and no correlation with switch region deletions was detected. No significant correlation between switch region deletions and prognosis was observed, indicating that internal deletions have no consequence for disease outcome. Moreover no significant correlation between the presence of switch deletions and somatic hypermutations was found, indicating that the two processes giving rise to internal deletions and somatic hypermutations, are independent in B-CLL.

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