Somatic hypermutation signature in B-cell low-grade lymphomas.
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.


METHODS
With the aim of identifying surrogate markers of somatic hypermutation, 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 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.
Tracey
Lorraine
L
Molecular Pathology Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.
Aggarwal
Mohit
M
García-Cosio
Mónica
M
Villuendas
Raquel
R
Algara
Patrocinio
P
Sánchez-Beato
Margarita
M
Sánchez-Aguilera
Abel
A
García
Juan F
JF
Rodríguez
Antonia
A
Camacho
Francisca I
FI
Martínez
Nerea
N
Ruiz-Ballesteros
Elena
E
Mollejo
Manuela
M
Piris
Miguel A
MA
D001402:B-Lymphocytes / Q000276:immunology; D043525:Cytosine Deaminase / Q000235:genetics; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D027041:Somatic Hypermutation, Immunoglobulin; D013154:Spleen / Q000276:immunology / Q000473:pathology
D004273:DNA, Neoplasm; D012334:RNA, Neoplasm; D043525:Cytosine Deaminase