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Blood, Vol. 95 No. 5 (March 1), 2000:
pp. 1797-1803
Molecular analysis of immunoglobulin genes in diffuse large B-cell
lymphomas
I. S. Lossos,
C. Y. Okada,
R. Tibshirani,
R. Warnke,
J. M. Vose,
T. C. Greiner, and
R. Levy
Division of Oncology, Department of Medicine, Department of Health
Research and Policy, and Department of Pathology, Stanford University
Medical Center, Stanford, CA; Department of Internal Medicine and
Department of Pathology, University of Nebraska Medical Center, Omaha,
NE.
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; VH
genes 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.
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