Prognostic alternative mRNA splicing in lung adenocarcinoma

Area of Science:

• Oncology
• Molecular Biology
• Bioinformatics

Background:

• Alternative splicing (AS) of mRNA plays a critical role in tumor progression and influences the tumor immune microenvironment (TIME).
• Lung adenocarcinoma (LUAD) is a major cause of cancer-related mortality, necessitating novel prognostic biomarkers.
• Understanding the link between AS and TIME is crucial for developing effective LUAD therapies.

Purpose of the Study:

• To develop an AS-based signature for accurate prognosis prediction in LUAD patients.
• To delineate the immune cell landscape associated with the AS signature.
• To identify potential drug targets for LUAD treatment.

Main Methods:

• Identified prognostic alternative splicing events (PASEs) using univariate Cox regression on TCGA RNA-Seq data.
• Developed a prognostic signature using a least absolute shrinkage and selection operator-Cox model.
• Validated the signature and investigated the role of CDKN2A using RT-qPCR, IHC, and in vitro/in vivo assays.

Main Results:

• A 13-PASE signature demonstrated strong predictive power for 1-, 2-, and 3-year overall survival (OS) in LUAD patients.
• High-risk patients exhibited altered immune cell infiltration, reduced immune activity, and decreased immune checkpoint gene expression.
• Elevated CDKN2A expression correlated with poorer OS, increased infiltration of specific immune cells, and promoted LUAD progression.

Conclusions:

• PASEs serve as comprehensive biomarkers for predicting prognosis and monitoring the TIME in LUAD.
• CDKN2A is a promising prognostic biomarker and potential therapeutic target for LUAD.
• YM-201636 and VE-822 show potential for targeting CDKN2A in LUAD treatment.