Molecular analysis of immunoglobulin genes in diffuse large B-cell lymphomas

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Abstract
Diffuse large B-cell lymphoma (DLBCL) is a common type of non-Hodgkin's lymphoma (NHL) that is highly heterogeneous from both clinical and histopathologic viewpoints. The immunoglobulin (Ig) heavy (H) chain variable region genes were examined in 71 patients with untreated primary DLBCL. Fifty-eight potentially functional VH genes were detected in 53 DLBCL cases; VHgenes were nonfunctional in 9 cases and were not detected in an additional 9 cases. The use of VH gene families by DLBCL tumors was unbiased without overrepresentation of any particular VH gene or gene family. Analysis of Ig mutations in comparison to the most closely related germline gene disclosed mutated VH genes in all but 1 DLBCL case. More than 2% difference from the most similar germline sequence was detected in 52 potentially functional and the 8 nonfunctional VH gene sequences, whereas less than 2% difference from the germline sequence was observed in 3 VH gene isolates. Only 3 VH gene isolates were unmutated. No correlation was found between VH gene use, mutation level, and International Prognostic Index (IPI) or survival. Six of 8 tested tumors showed evidence of ongoing somatic mutations. Evidence for positive or negative antigen selection pressure was observed in 65% of mutated DLBCL cases. Our findings indicate that the etiology and the driving forces for clonal expansion are heterogeneous, which may explain the well-known clinical and pathologic heterogeneity of DLBCL.