CLONAL HISTORY OF A HUMAN FOLLICULAR LYMPHOMA AS REVEALED IN THE IMMUNOGLOBULIN VARIABLE REGION GENES

The variable region genes used to encode the immunoglobulin expressed by tumour cells of a patient with follicular lymphoma have been identified and sequenced. Initially, a lymph node biopsy was analysed and revealed usage of V-H and V(k)appa genes which had numerous substitutions as compared with the closest germ line genes. The pattern of mutations in VH was consistent with a role for positive selection by antigen. In addition, there was evidence in both V-H and V(k)appa sequences for clonal heterogeneity. After 5 years, which included treatment with chemotherapy, the patient relapsed with tumour cells present in the blood. Analysis of the V-genes used by the emerging tumour revealed a single homogeneous sequence for both V-H and V-L. which, in each case, matched closely one of the sequences in the original lymph node biopsy. These results indicate that selection, possibly mediated by antigen, can operate on a cell destined to give rise to lymphoma, and that intraclonal variation can occur after the neoplastic event. However, in this case, late relapse in the blood is dominated by a single clone.