Framing the potential of public frameshift peptides as immunotherapy targets in colon cancer

Area of Science:

• Oncology
• Genomics
• Immunotherapy

Background:

• Microsatellite Instability (MSI) occurs in approximately 15% of colon cancers.
• Frameshift Peptides (FPs) arising from MSI are potential targets for cancer immunotherapy.
• Understanding the mutational landscape of MSI cancers is crucial for developing targeted therapies.

Purpose of the Study:

• To comprehensively characterize the mutational landscape of MSI colon cancer.
• To identify novel frameshift peptides (FPs) as potential targets for immunotherapy.
• To assess the prevalence and therapeutic potential of these FPs across different MSI-driven cancers.

Main Methods:

• Analysis of whole-exome sequencing data from 71 MSI colon cancer patients from The Cancer Genome Atlas (TCGA).
• Identification and filtering of frameshift mutations based on variant allele frequency, mRNA levels, and Super Neo Open Reading Frame (SNORF) formation.
• Evaluation of Nonsense Mediated Decay (NMD) escape using RNA and DNA sequencing data.

Main Results:

• Confirmed frequent frameshift deletions (23%) in MSI colon cancers, clustering at specific genomic locations.
• Identified 20 NMD-escaping Public FPs (PFPs) that are highly prevalent in MSI colon cancer (90%).
• Demonstrated PFP coverage in other MSI cancers (endometrial, stomach) and Lynch syndrome patients.

Conclusions:

• A set of 20 Public FPs (PFPs) represents promising targets for immunotherapy in MSI cancers.
• These PFPs have broad applicability across various MSI-driven malignancies, including colon, endometrial, and stomach cancers.
• PFP-directed immunotherapy holds potential for both therapeutic and prophylactic applications in MSI cancers.