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Somatic hypermutation signature in B-cell low-grade lymphomas

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

ABSTRACT

Background: Immunoglobulin gene somatic hypermutation (SHM) 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 SHM, a combined investigation of IgV_H mutational status and expression profiles of 93 samples from patients with small B-cell lymphoma was performed.

Results: The analysis identified an SHM 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 SHM 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 SHM (p<0.001). To assess the potential clinical applicability of these SHM 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 SHM 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.