Mutation of CMTR2 in Lung Adenocarcinoma Alters RNA Alternative Splicing and Reveals Therapeutic Vulnerabilities

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• RNA splicing dysregulation is a key feature of cancer, but its comprehensive role in solid tumors is not fully understood.
• Understanding splicing patterns is crucial for identifying new therapeutic targets in cancer treatment.

Purpose of the Study:

• To characterize the alternative splicing landscape in lung adenocarcinoma.
• To identify novel molecular subtypes and potential therapeutic vulnerabilities associated with splicing alterations.

Main Methods:

• Alternative splicing analysis of RNA-sequencing data from 751 lung adenocarcinoma samples and 519 The Cancer Genome Atlas samples.
• Visualization of splicing patterns using t-distributed stochastic neighbor embedding (t-SNE).
• Functional validation of mutations using CRISPR-Cas9 gene editing.

Main Results:

• Significant inter-tumor heterogeneity in splicing patterns was observed, linked to molecular subtypes and differentiation.
• A distinct molecular subtype characterized by inactivating mutations in CMTR2 (Cap-specific mRNA (nucleoside-2'-O-)-methyltransferase 2) was identified.
• CMTR2 mutations disrupt alternative splicing, leading to sensitization of cancer cells to RNA splicing modulators and immune checkpoint blockade therapy.

Conclusions:

• A previously unrecognized RNA splicing deficiency driven by CMTR2 mutations defines a new subtype of lung adenocarcinoma.
• CMTR2-deficient tumors show increased sensitivity to immune checkpoint blockade therapy, suggesting a potential therapeutic strategy.
• These findings highlight RNA splicing dysregulation as a critical factor in lung cancer and offer new targets for intervention.