Abstract
Aberrant somatic hypermutation (aSHM) can target proto-oncogenes and drive oncogenesis. In mantle cell lymphoma (MCL), CCND1 is targeted by aSHM in the non-nodal subtype (nnMCL), giving rise to exon1 encoded mutant proteins like E36K, Y44D, and C47S that contribute to lymphomagenesis by virtue of their increased protein stability and nuclear localization. However, the vast majority of somatic variants generated by aSHM are found in the first intron of CCND1 but their significance for mantle cell lymphomagenesis is unknown. We performed whole-genome and whole-transcriptome sequencing in 84 MCL patients to explore the contribution of non-coding somatic variants created by aSHM to lymphomagenesis. We show that non-coding variants are enriched in a MCL specific manner in transcription factor-binding sites, that non-coding variants are associated with increased CCND1 mRNA expression, and that coding variants in the first exon of CCND1 are more often synonymous or cause benign amino acid changes than in other types of lymphomas carrying a t(11;14) translocation. Therefore, the increased frequency of somatic variants due to aSHM might be a consequence of selection pressure manifested at the transcriptional level rather than being a mere mechanistic consequence of misguided activation-induced cytidine deaminase (AID) activity.
Highlights
Mantle cell lymphoma (MCL) is an aggressive B cell neoplasm genetically characterized by the translocation t(11;14)(q13;q32), leading to CCND1 overexpression [1, 2]
We report that CCND1 mutations generated by Aberrant somatic hypermutation (aSHM) are frequently observed in MCL as compared to other lymphomas carrying the t(11;14)(q13;q32) translocation
Description Atypical chronic myeloid leukemia Acute myeloid leukemia Acute undifferentiated leukemia B cell precursor acute lymphoblastic leukemia B cell non-Hodgkin’s lymphoma Blastic plasmacytoid dendritic cell neoplasm Chronic lymphocytic leukemia Chronic myeloid leukemia Chronic myelomonocytic leukemia Follicular lymphoma Hairy cell leukemia High-grade B cell lymphoma Lymphoplasmacytic lymphoma Mastocytosis Mantle cell lymphoma Myelodysplastic syndrome Myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis Myelodysplastic/myeloproliferative neoplasms, unclassifiable IgM monoclonal gammopathy of undetermined significance Myeloid or lymphoid neoplasms associated with eosinophilia Multiple myeloma Mixed-phenotype acute leukemia Myeloproliferative neoplasm Marginal zone lymphoma Natural killer cell neoplasm Paroxysmal nocturnal hemoglobinuria Polyclonal B cell lymphocytosis T cell acute lymphoblastic leukemia T cell non-Hodgkin’s lymphoma Hairy cell leukemia variant
Summary
Mantle cell lymphoma (MCL) is an aggressive B cell neoplasm genetically characterized by the translocation t(11;14)(q13;q32), leading to CCND1 overexpression [1, 2]. Two molecular subtypes are currently recognized: (1) Classical MCL (cMCL) is composed of B cells with minimally mutated or unmutated immunoglobulin heavy chain variable (IGHV) region that express SOX11. Patients have generalized lymphadenopathy and the outcome is adverse. (2) In non-nodal MCL (nnMCL), B cells do not express SOX11 and often carry mutated IGHV. The involved organs are peripheral blood, bone marrow, and spleen. Cases are often clinically indolent [1]. The cells of origin are believed to be naive B cells that do not undergo germinal center reactions as in the case of cMCL and memory B cells in nnMCL [3]
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