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Analysis of VH Genes in Follicular and Diffuse Lymphoma
Shows Ongoing Somatic Mutation and Multiple Isotype Transcripts in
Early Disease With Changes During Disease Progression
Christian H. Ottensmeier,
Andrew R. Thompsett,
Delin Zhu,
Bridget S. Wilkins,
John W. Sweetenham, and
Freda K. Stevenson
From the Molecular Immunology Group, Tenovus Laboratory, Southampton;
and the Departments of Pathology and Medical Oncology, Southampton
University Hospitals, Southampton, UK.
Investigations of VH gene mutational patterns in B-cell
tumors are often performed at an arbitrary time point of disease. To
assess the effects of disease progression, tumor-derived VH genes have been monitored from presentation through treatment and
relapse in one patient with follicle center lymphoma (FCL), and two
patients with primary diffuse large B-cell lymphoma (DLCL). The patient
with FCL and one patient with DLCL both achieved clinical remission,
although this was only partial in the FCL. However, both subsequently
relapsed, and the second patient with DLCL was refractory to
radiotherapy and chemotherapy. In each case, the tumor-derived
VH sequence was identified, and the CDR3 "clonal signature" was used to track tumor cell sequences in subsequent biopsies. All cases showed somatic mutations, with intraclonal heterogeneity evident at presentation, and some sequences were aberrant. The VH sequences of the DLCL which responded to
treatment became homogeneous at relapse. The sequences of both the FCL
and the refractory DLCL remained heterogeneous. In all cases,
transcripts of multiple Ig isotypes could be identified, and there was
immunophenotypic evidence for expression of several Ig isotypes. The
case of refractory DLCL had identifiable transcripts from IgM, IgD,
IgA, IgG, and IgE, but appeared to lose the ability to produce
alternative isotype transcripts and protein at the late stage of
disease. These cases indicate that VH gene analysis can be
used to probe tumor cell behavior in cases of lymphoma and that
perturbations caused by therapy and disease progression can occur.
Blood, Vol. 91 No. 11 (June 1), 1998:
pp. 4292-4299
© 1998 by The American Society of Hematology.
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