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Expression of NOTCH3 exon 16 differentiates Diffuse Large B-cell Lymphoma into molecular subtypes and is associated with prognosis

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, il...

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Autores principales: Jespersen, Ditte Starberg, Schönherz, Anna A., Due, Hanne, Bøgsted, Martin, Sondergaard, Teis Esben, Dybkær, Karen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6344585/
https://www.ncbi.nlm.nih.gov/pubmed/30674940
http://dx.doi.org/10.1038/s41598-018-36680-x
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author Jespersen, Ditte Starberg
Schönherz, Anna A.
Due, Hanne
Bøgsted, Martin
Sondergaard, Teis Esben
Dybkær, Karen
author_facet Jespersen, Ditte Starberg
Schönherz, Anna A.
Due, Hanne
Bøgsted, Martin
Sondergaard, Teis Esben
Dybkær, Karen
author_sort Jespersen, Ditte Starberg
collection PubMed
description 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.
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spelling pubmed-63445852019-01-28 Expression of NOTCH3 exon 16 differentiates Diffuse Large B-cell Lymphoma into molecular subtypes and is associated with prognosis Jespersen, Ditte Starberg Schönherz, Anna A. Due, Hanne Bøgsted, Martin Sondergaard, Teis Esben Dybkær, Karen Sci Rep Article 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. Nature Publishing Group UK 2019-01-23 /pmc/articles/PMC6344585/ /pubmed/30674940 http://dx.doi.org/10.1038/s41598-018-36680-x Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Jespersen, Ditte Starberg
Schönherz, Anna A.
Due, Hanne
Bøgsted, Martin
Sondergaard, Teis Esben
Dybkær, Karen
Expression of NOTCH3 exon 16 differentiates Diffuse Large B-cell Lymphoma into molecular subtypes and is associated with prognosis
title Expression of NOTCH3 exon 16 differentiates Diffuse Large B-cell Lymphoma into molecular subtypes and is associated with prognosis
title_full Expression of NOTCH3 exon 16 differentiates Diffuse Large B-cell Lymphoma into molecular subtypes and is associated with prognosis
title_fullStr Expression of NOTCH3 exon 16 differentiates Diffuse Large B-cell Lymphoma into molecular subtypes and is associated with prognosis
title_full_unstemmed Expression of NOTCH3 exon 16 differentiates Diffuse Large B-cell Lymphoma into molecular subtypes and is associated with prognosis
title_short Expression of NOTCH3 exon 16 differentiates Diffuse Large B-cell Lymphoma into molecular subtypes and is associated with prognosis
title_sort expression of notch3 exon 16 differentiates diffuse large b-cell lymphoma into molecular subtypes and is associated with prognosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6344585/
https://www.ncbi.nlm.nih.gov/pubmed/30674940
http://dx.doi.org/10.1038/s41598-018-36680-x
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