Low transcript expression levels of a specific NOTCH3 splice variant, NOTCH3 excluding exon 16 (NOTCH3 – exon 16), show potential as a negative prognostic biomarker that may also be predictive of vincristine resistance in patients classified as having germinal center B cell (GCB) diffuse large B-cell lymphoma (DLBCL), according to a study published in Scientific Reports

The heterogeneous nature of DLBCL, characterized by diverse clinical presentations, cellular morphological and molecular characteristics, response to chemotherapy, and survival outcomes, has led to the development of a number of DLBCL classification systems. In order to enhance risk stratification of patients with DLBCL, researchers investigated whether alternative events in mRNA splicing and exon usage could serve as potential biomarkers. Previous molecular studies of the role of NOTCH genes as drivers of hematological malignancies have typically been focused at the DNA level. 

A retrospective analysis determined baseline characteristics and disease subtype classifications of 75 patients with DLBCL. Alternatively spliced genes were identified in 37 DLBCL specimens. Loss of exon 16 in NOTCH3 transcripts was observed for the GCB-centroblast subtype, but not the GCB-centrocyte subtype.  Interestingly, DNA analyses of NOTCH3 did not distinguish the GCB-centroblast and GCB-centrocyte subtypes. In addition, higher expression levels of the NOTCH3 – exon 16 transcript were associated with higher sensitivity to vincristine in GCB-classified patients. While expression levels of NOTCH3 – exon 16 transcripts were not demonstrated to have independent prognostic significance in DLBCL, a trend for association of overall survival for R-CHOP treated patients and NOTCH3 – exon 16 expression level was observed within the GCB subclass (P =.07). 

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“This pilot study indicates that altered alternative splicing contributes to the pathogenesis of DLBCL depending on the molecular subtypes and may be promising as prognostic and predictive biomarkers,” the authors concluded. “More studies using a larger independent patient cohort are required to confirm the impact of the NOTCH3 – exon 16 transcript on overall survival of GCB DLBCL patients.”

Reference

  1. Jespersen DS, Schönherz AA, Due H, Bøgsted M, Sondergaard TE, Dybkær K. Expression of NOTCH3 exon 16 differentiates Diffuse Large B-cell Lymphoma into molecular subtypes and is associated with prognosis. Sci Rep. 2019;9(1):335. doi: 10.1038/s41598-018-36680-x