Published online 12 June 2008
Haematologica, Vol 93, Issue 8, 1186-1194 doi:10.3324/haematol.12999
Copyright © 2008 by Ferrata Storti Foundation
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Tracey et al. - Supplementary appendix
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Tracey, L.
Right arrow Articles by Piris, M. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tracey, L.
Right arrow Articles by Piris, M. A.

Malignant Lymphomas

Somatic hypermutation signature in B-cell low-grade lymphomas

Lorraine Tracey1, Mohit Aggarwal1, Mónica García-Cosio2, Raquel Villuendas1, Patrocinio Algara3, Margarita Sánchez-Beato1, Abel Sánchez-Aguilera1, Juan F. García4, Antonia Rodríguez5, Francisca I. Camacho6, Nerea Martínez1, Elena Ruiz-Ballesteros3, Manuela Mollejo3, Miguel Á. Piris1

1 Molecular Pathology Programme, Centro Nacional de Investigaciones Oncológicas, Madrid
2 Pathology Department, Hospital Ramon y Cajal, Madrid
3 Genetics and Pathology Departments, Hospital Virgen de la Salud, Toledo
4 Pathology Department, MD Anderson International Spain, Madrid
5 Hematology Department, Hospital Doce de Octubre, Madrid
6 Pathology Department, Hospital Universitario de Getafe, Madrid, Spain

Correspondence: Miguel A. Piris, Centro Nacional de Investigaciones Oncológicas, Melchor Fernández Almagro, 3, Madrid 28029, Spain. E-mail:mapiris{at}cnio.es

Background: Immunoglobulin gene somatic hypermutation is a biologically relevant and clinically useful prognostic factor in different types of low-grade B-cell lymphomas, including chronic lymphocytic leukemia, mantle cell lymphoma and splenic marginal zone lymphoma.

Design and Methods: With the aim of identifying surrogate markers of somatic hypermutation, a combined investigation of IgVH mutational status and expression profiles of 93 samples from patients with small B-cell lymphoma was performed.

Results: The analysis identified an somatic hypermutation signature of genes involved in the regulation of gene transcription, DNA repair and replication, and chromosome maintenance. Eight of these genes were subjected to protein analysis using tissue microarrays, for a set of 118 cases. We found a clear link between RAD51C and CDK7 protein expression and somatic hypermutation status, in that positive expression of either marker was significantly associated with a mutated status (p<0.003). We also found that positive expression of TFDP1 and POLA was significantly associated with ongoing somatic hypermutation (p<0.001). To assess the potential clinical applicability of these somatic hypermutation markers, we studied a series of cases of mantle cell lymphoma included in a tissue microarray. The expression of RCC1 and CDK7, separately and together, was found to be significantly associated with longer overall survival.

Conclusions: An somatic hypermutation signature has been identified for different types of small B-cell lymphoma. This has a potential mechanistic and diagnostic value.

Key words: lymphomas, somatic hypermutation, profiling.