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Updated: Aug 28, 2025
Author Spotlight: Advancing Early Detection and Treatment of Gastrointestinal Tumors
Published on: February 16, 2024
Landscape of exitrons in gastric cancer
Yihao Zhang1, Gengtai Ye1, Qingbin Yang1
1Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, Guangdong 510515, China; Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Guangzhou, Guangdong 510515, China.
Background:
Exitron is a new type of non-canonical alternative splicing. Accumulating evidence implies exitron may have pathological function and contribute to another source of anti-tumor immunogenicity in various cancers. Its role in gastric cancer remains poorly understood. Large-scale, multi-omics analysis could comprehensively characterize the landscape of exitrons in gastric cancer, reveal undiscovered mechanism and hopefully identify molecular biomarkers for predicting immunotherapy response.
Methods:
We collected datasets from five studies for analysis. RNA sequencing was used for exitron identification. Somatic mutations were detected by whole exome sequencing. Neopeptides were confirmed by proteome mass spectrometry.
Findings:
42174 gastric cancer-specific exitrons (GCSEs) were identified in 632 patients. GCSEs were clinically relevant to gender, age, Lauren type, tumor stage and prognosis. Tissue specificity test and pathogenic exitron prediction revealed their unique functional impact. GCSEs were mutually exclusive with mutations and demonstrated both unique and complementary function against TP53 mutation in gastric cancer. We further established splicing regulatory network to reveal upstream regulation of exitron splicing. We also evaluated the immunogenicity and diagnostic potential of GCSEs. Evidence of GCSEs-derived neopeptide expression was validated by whole proteome mass spectrometry. PD-1 and Siglecs were significantly increased in high neoantigen load patients. But exitron-related biomarkers failed to predict immunotherapy response, possibly due to small sample size and insufficient sequencing depth.
Interpretation:
The present study provided a comprehensive multidimensional landscape of gastric cancer exitrons and underscores insights into underexplored mechanism in gastric cancer pathology.
Funding:
The Guangdong Provincial Key Laboratory of Precision Medicine for Gastroinstestinal Cancer (2020B121201004), the Guangdong Provincial Major Talents Project (No. 2019JC05Y361) and National Natural Science Foundation of China (grant number:82172960 and 81872013).
Insights
This study identified 42,174 gastric cancer-specific exitrons (GCSEs), revealing their clinical relevance and potential role in tumor pathology. While GCSEs showed immunogenic properties, they did not predict immunotherapy response in gastric cancer patients.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Exitrons, a novel class of non-canonical alternative splicing events, are implicated in cancer pathology and anti-tumor immunity.
- The role and landscape of exitrons in gastric cancer remain largely unexplored.
- Multi-omics analysis offers a comprehensive approach to characterize exitrons in gastric cancer and identify potential biomarkers.
Purpose of the Study:
- To comprehensively characterize the landscape of exitrons in gastric cancer using large-scale, multi-omics data.
- To investigate the clinical relevance, functional impact, and immunogenicity of gastric cancer-specific exitrons (GCSEs).
- To explore the potential of GCSEs as molecular biomarkers for predicting immunotherapy response in gastric cancer.
Main Methods:
- Collected and analyzed datasets from five studies.
- Identified exitrons using RNA sequencing.
- Detected somatic mutations via whole exome sequencing and confirmed neopeptides using proteome mass spectrometry.
Main Results:
- Identified 42,174 gastric cancer-specific exitrons (GCSEs) in 632 patients.
- GCSEs demonstrated clinical relevance to patient demographics, tumor characteristics, and prognosis.
- GCSEs exhibited unique and complementary functions against TP53 mutations and showed immunogenic potential, though they failed to predict immunotherapy response.
Conclusions:
- Provided a comprehensive landscape of gastric cancer exitrons.
- Underscored novel insights into the mechanisms of gastric cancer pathology related to exitrons.
- Highlighted the need for further research to validate GCSEs as biomarkers, potentially with larger sample sizes and deeper sequencing.
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