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

Ditte Starberg Jespersen, Anna A Schönherz, Hanne Due, Martin Bøgsted, Teis Esben Sondergaard, Karen Dybkær

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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Resumé

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.

OriginalsprogEngelsk
Artikelnummer335
TidsskriftScientific Reports
Vol/bind9
Udgave nummer1
ISSN2045-2322
DOI
StatusUdgivet - jan. 2019

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Lymphoma, Large B-Cell, Diffuse
Exons
Biomarkers
Vincristine
Genes
Alternative Splicing
Oncogenes
Carcinogenesis
B-Lymphocytes
Down-Regulation
Survival

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

I: Scientific Reports, Bind 9, Nr. 1, 335, 01.2019.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

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AU - Jespersen, Ditte Starberg

AU - Schönherz, Anna A

AU - Due, Hanne

AU - Bøgsted, Martin

AU - Sondergaard, Teis Esben

AU - Dybkær, Karen

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N2 - 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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