Higher-grade transformation of follicle center lymphoma is associated withsomatic mutation of the 5 ' noncoding regulatory region of the BCL-6 gene

Follicle center lymphoma (FCL) is an indolent low-grade B-cell non-Hodgkin' s lymphoma (NHL) that frequently transforms to aggressive diffuse large B-c ell lymphoma (DLBCL), Histologic transformation of FCL is commonly associat ed with accumulation of secondary genetic alterations, The BCL-6 gene is al tered by chromosomal rearrangements and mutations clustering in its 5' nonc oding regulatory region In up to 70% of primary DLBCL, but in a significant ly smaller subset of FCL, Previous studies have shown that both chromosomal rearrangements and mutations could deregulate BCL-6 expression, To evaluat e the association between progressive accumulation of BCL-6 regulatory regi on mutations and the histologic transformation of FCL, we analyzed by exten sive cloning and sequencing paired biopsy specimens obtained at the time of FCL diagnosis and transformation (6 patients) or FCL relapse (3 patients). In an additional patient, biopsy specimens obtained at the time of diagnos is, FCL relapse, and subsequent transformation to DLBCL were evaluated. The presence of identical mutations in the paired diagnosis and posttransforma tion DLBCL specimens confirmed the common clonal origin of both the pretran sformation and the posttransformation lymphomas, No new mutations in the 5' noncoding regulatory region of the BCL-6 gene were detected In any of the specimens evaluated at the time of FCL relapse, In contrast, 5 of the 7 tra nsformed specimens contained new mutations not found in the paired original biopsy specimens obtained at the time of FCL diagnosis or relapse, The num ber of these new mutations ranged from 1 to 6 per specimen, Some of the new mutations tended to cluster in certain areas of the 5' noncoding regulator y region of the BCL-6 gene, Our results show that transformation of FCL to DLBCL is associated with accumulation of new mutations in the 5' noncoding regulatory region of the BCL-6 gene, that by deregulation of the BCL-6 gene expression may play a role in lymphoma transformation, (C) 2000 by The Ame rican Society of Hematology.