Abstract
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with diverse clinical presentation and outcome. Bio-clinical prognostic models including oncogene expression and cell-of-origin phenotyping has been developed, however, approximately 30% of all patients still die from their disease, illustrating the need for additional prognostic biomarkers associating oncogenesis and phenotypic subclasses. Hence, we tested if alternative splice variations have biomarker potential. Initial alternative splicing analysis of human exon array from clinical DLBCL samples identified candidate genes. Experimental validation by ddPCR was performed in a DLBCL cohort classified into ABC/GCB subclasses, B-cell associated gene signatures (BAGS: naive, centroblast, centrocyte, memory, and plasmablast), and vincristine resistant gene signatures. Prognostic potential was assessed for aberrantly spliced transcripts. Thus, NOTCH3 was identified as alternatively spliced, with differential exon 16 depletion (−exon 16) between differentiation associated BAGS subtypes. Predicted vincristine resistant patients of the GCB subclass had significantly downregulated NOTCH3 −exon 16 transcript expression and tended to display adverse overall survival for R-CHOP treated patients. In conclusion, we have identified a specific alternatively spliced NOTCH3 event that differentiate molecular subtypes of DLBCL and display prognostic and predictive biomarker potential in GCB DLBCL.
Highlights
Diffuse large B-cell lymphoma (DLBCL) is the most frequent lymphoid neoplasm among adults, accounting for 30% to 40% of all Non-Hodgkin’s lymphomas[1]
We identified NOTCH3 as an alternatively spliced gene and subsequently experimentally validated the biomarker potential in a primary DLBCL cohort
Patients were classified into molecular subtypes of DLBCL using gene expression profiling (GEP)-based classifications, activated B-cell (ABC)/germinal center B-cell (GCB) and B-cell associated gene signatures (BAGS), which based on the B-cell degree of differentiation risk stratify DLBCL patients[7,8] and resistance gene signature (REGS) predicting vincristine response[9]
Summary
Diffuse large B-cell lymphoma (DLBCL) is the most frequent lymphoid neoplasm among adults, accounting for 30% to 40% of all Non-Hodgkin’s lymphomas[1]. Based on gene expression profiling (GEP) DLBCL patients are classified into molecular subclasses with inherent prognostic impact: e.g. the ABC/GCB, the B-cell associated gene signature (BAGS) or the resistance gene signature (REGS) classification systems[7,8,9]. The ABC/GCB subclasses differ in pathogenesis and survival outcome with ABC classified patients having an impaired 5-year survival rate compared to those classified as GCB when treated with R-CHOP7. The BAGS classification is a refined cell-of-origin classification system where primary tumors at time of diagnosis are associated with normal B-cell subset phenotypes and classified into naive, centroblast, centrocyte, memory, and plasmablast B-cell subtypes providing additional prognostic information to molecular ABC/ GCB subclasses. Different activated signalling pathways, genetic profiles, and responses to chemotherapeutic drugs used in treatment of DLBCL is observed for the BAGS subtypes[8,9]
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