Published online 22 October 2008
Haematologica, Vol 93, Issue 12, 1822-1828 doi:10.3324/haematol.13239
Copyright © 2008 by Ferrata Storti Foundation

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Malignant Lymphomas

Somatic hypermutation of IGVH genes and aberrant somatic hypermutation in follicular lymphoma without BCL-2 gene rearrangement and expression

Éva Gagyi, Zsófia Balogh, Csaba Bödör, Botond Timár, Lilla Reiniger, Linda Deák, Judit Csomor, Balázs Csernus, Ágota Szepesi, András Matolcsy

First Department of Pathology and Experimental Cancer Research, Faculty of Medicine, Semmelweis University, Budapest, Hungary

Correspondence: András Matolcsy M.D., PhD., 1^st Department of Pathology and Experimental Cancer Research, Faculty of Medicine, Semmelweis University, H-1085 Budapest, Üllöi út 26, Hungary. E-mail:matolcsy{at}korb1.sote.hu

Background: Follicular lymphoma is characterized by the t(14;18) translocation resulting in constitutive expression of BCL-2 protein; however approximately 10–15% of follicular lymphomas do not express BCL-2 protein, and a small fraction of these cases does not exhibit translocation of the BCL-2 gene either. It is highly debated whether cases of follicular lymphoma without BCL-2 gene rearrangement and expression represent a separate lymphoma entity with distinct biological characteristics, different from the BCL-2-positive cases.

Design and Methods: To further characterize follicular lymphomas without BCL-2 gene rearrangement and expression, we analyzed and compared the mutational status of IGVH genes as well as other genes (C-MYC, PAX-5 and RHOH) frequently involved in the specific type of genomic instability called aberrant somatic hypermutation in 11 cases of BCL-2-negative and 7 cases of BCL-2-positive follicular lymphomas. We also determined the levels of expression of activation-induced cytidine deaminase in these cases.

Results: The analyzed cases were grade 2 and grade 3A follicular lymphomas. Our findings demonstrate that follicular lymphomas without BCL-2 gene rearrangement and expression are associated with ongoing somatic hypermutation of the IGVH genes, low activity of aberrant somatic hypermutation and elevated activation-induced cytidine deaminase expression. These results were in concordance with the results found in the cases of BCL-2-positive follicular lymphoma.

Conclusions: Although, BCL-2 protein overexpression is considered to be a critical pathogenic event in the development of follicular lymphoma, our findings suggest that follicular lymphomas with the same morphology, immunophenotype, mutational pattern and activation-induced cytidine deaminase expression may develop without the involvement of BCL-2 gene. The present data support the hypothesis that BCL-2-positive and BCL-2-negative follicular lymphomas (grades 1-3A) represent a homogenous group with different initial but several common additional molecular pathways.

Key words: follicular lymphoma, somatic hypermutation, aberrant somatic hypermutation, activation-induced cytidine deaminase.

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