Alternative splicing discriminates molecular subtypes and has prognostic impact in diffuse large B-cell lymphoma

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• Alternative splicing (AS) plays a crucial role in cellular processes, but its impact on diffuse large B-cell lymphoma (DLBCL) pathogenesis and survival remains underexplored.
• DLBCL is a heterogeneous disease with distinct molecular subtypes, including germinal center B-cell like (GCB) and activated B-cell like (ABC), which exhibit different clinical behaviors.

Purpose of the Study:

• To systematically investigate the effect of alternative splicing on DLBCL pathogenesis and patient survival.
• To compare gene and exon expression profiles to identify AS events associated with survival and molecular subtypes in DLBCL.

Main Methods:

• Genome-wide exon array screening was performed on 38 high-risk DLBCL patients treated with dose-dense chemoimmunotherapy.
• Pathway analysis was conducted to identify biological processes enriched in AS genes.
• Validation of differential exon usage and AS association with subtypes and survival was performed using RNA-sequencing on an independent cohort of 92 DLBCL samples.

Main Results:

• Exon expression profiles provided better separation of DLBCL molecular subgroups and survival prediction compared to gene expression profiles.
• AS genes were significantly enriched in inflammation, adhesion, signal transduction pathways, including phosphatidylinositol signaling and ABC transporters.
• 49% of AS-related exons were protein-coding, with 28% including functional domains, such as transmembrane helix domains or phosphorylation sites.
• Validation confirmed differential exon usage and its association with DLBCL molecular subtypes and survival.

Conclusions:

• Alternative splicing events are capable of discriminating between GCB and ABC DLBCL subtypes.
• AS has a significant prognostic impact in DLBCL, suggesting its potential as a biomarker for patient stratification and treatment guidance.