Analysis of expressed immunoglobulin heavy chain genes in familial B-CLL

In this study, we wished to determine whether familial chronic lymphocytic leukemia of B-cell phenotype (CLL) shares with sporadic B-CLL the same immu noglobulin (Ig) heavy chain variable region (VH) gene usage and occurrence of somatic mutation, to gain insight into the pathogenetic relatedness of t hese epidemiologically distinct forms of CLL. We therefore analyzed the exp ressed Ig heavy chain genes in 23 cases (11 families) of familial CLL, and compared these results with data previously reported for sporadic CLL, In a ddition, we assessed the relationship of the occurrence of somatic mutation to several clinical and phenotypic features. The distribution of V genes a mong these cases was similar to that observed in sporadic CLL: VH3 > VH1 > VH4. Thirteen of the 23 cases (57%) showed germ line VH gene sequences, whe reas somatic mutations were detected in 10 cases (43%), The average mutatio n frequency of these latter 10 cases of was 6.7% (ranging from 1.7% to 8.8% ), and evidence of antigen selection was noted in 6. Intraclonal variation, followed by clonal evolution and the appearance of a second clone over a 2 0 year period was observed in 1 case, suggesting that mutations can continu e to accumulate after neoplastic transformation. The presence of somatic mu tations correlated with age at presentation, low white blood cell (WBC) cou nt, and low fluorescence intensity of surface CD5, and the potential signif icance of these relationships is discussed. Our data indicate that familial end sporadic B-CLL display a similar pattern of immunoglobulin gene usage and frequency of somatic mutation, and are consistent with a common ontogen y and immunogenetic origin for these 2 epidemiologically distinct forms of CLL. (C) 2000 by The American Society of Hematology.