Insight into the origin and clonal history of B‐cell tumors as revealed by analysis of immunoglobulin variable region genes

Abstract

Summary: Recombination of V_H D_H and J_H genes is a unique first step in normal B‐cell development. Subsequent differentiation to a mature plasma cell is accompanied by further events in the Ig genes, including V_I‐J_t joining, somatic hypermutation and isotype switching. Chromosomal changes leading to B‐cell tumors can occur at many points in this sequence, and may be partly a consequence of the genetic mobility and mutability permitted in order to generate a diverse antibody repertoire, V genes of neo‐plastic B cells may reflect the point of maturation reached by the B cell of origin, prior to transformation, Analysis of tumors therefore provides useful information on V‐gene patterns in normal B cells, and may add another dimension to classification of B‐cell tumors. Transformation ma)’ also preserve cell populations normally destined to die by apoptosis. Tumor cells arrested in the sire where somatic hypermutation and isotype switch are occurring can still be subject to these processes, and could be influenced by persisting antigen. However, mutation is silenced at the point of exit lo the periphery, leading lo fixed mutational patterns in tumors of mature B cells, V‐gene analysis provides an invaluable tool for understanding the genesis of neoplastic change. It also has a clear clinical relevance in tracking tumor cells, measuring residual disease, and finally in offering the opportunity of developing vaccines for treatment.