Ongoing immunoglobulin gene mutations in mantle cell lymphomas.

Abstract

Mantle cell lymphomas (MCL) frequently show a vaguely follicular growth pattern. This phenomenon is thought to result from the colonization of reactive B-cell follicles by tumour cells. In view of the unique property of the germinal centre environment, antigen stimulation may play a role in the expansion of the tumour. To assess this, we have examined ongoing Ig mutations, which are genetic markers of B cells in persistent response to antigen stimulation, in five MCLs including two cases derived from the gastrointestinal tract known as lymphomatous polyposis (LP). We have specifically analysed Ig ongoing mutations in tumour cells from multiple lesions in one case and in tumour cells microdissected from colonized follicles in two cases. The consensus Ig VB sequences in four MCLs were identical, or almost identical (three cases 100%, one case 99% homology), to the published germlines, which in each case were those frequently employed by autoantibodies. The consensus Ig VH sequence in the remaining case displayed 95.5% homology to the closest published germline. This may represent derivation from an unknown VH germline or a rare instance of somatic mutations. Extensive sequencing of the rearranged Ig genes revealed ongoing mutations within the tumour clone in two cases: one was a LP with multiple lesions of the gastrointestinal tract and the other was a nodal MCL in which tumour cells from colonized follicles were analysed. Our results indicate that MCLs are derived from pre-germinal centre B cells, possibly autoreactive B-cell clones. The ongoing mutations identified suggest a possible involvement of antigen stimulation in the clonal expansion of a proportion of MCLs.