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

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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.

In: Scientific Reports, Vol. 9, 335, 12.2019.

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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. In: Scientific Reports. 2019 ; Vol. 9.

Bibtex

@article{469d33b8b7184e44892fbd938c225421,
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.",
keywords = "CANCER, CLASSIFICATION, MUTATIONS, RESISTANCE, SUBSET, SURVIVAL",
author = "Jespersen, {Ditte Starberg} and Sch{\"o}nherz, {Anna A} and Hanne Due and Martin B{\o}gsted and Sondergaard, {Teis Esben} and Karen Dybk{\ae}r",
year = "2019",
month = "12",
doi = "10.1038/s41598-018-36680-x",
language = "English",
volume = "9",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",

}

RIS

TY - JOUR

T1 - Expression of NOTCH3 exon 16 differentiates Diffuse Large B-cell Lymphoma into molecular subtypes and is associated with prognosis

AU - Jespersen, Ditte Starberg

AU - Schönherz, Anna A

AU - Due, Hanne

AU - Bøgsted, Martin

AU - Sondergaard, Teis Esben

AU - Dybkær, Karen

PY - 2019/12

Y1 - 2019/12

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.

AB - 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.

KW - CANCER

KW - CLASSIFICATION

KW - MUTATIONS

KW - RESISTANCE

KW - SUBSET

KW - SURVIVAL

UR - http://www.scopus.com/inward/record.url?scp=85060387994&partnerID=8YFLogxK

U2 - 10.1038/s41598-018-36680-x

DO - 10.1038/s41598-018-36680-x

M3 - Journal article

C2 - 30674940

VL - 9

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 335

ER -