Related Experiment Video
Updated: Aug 22, 2025
Genome-Wide Analysis of DNA Methylation in Gastrointestinal Cancer
Published on: September 18, 2020
PIK3CA somatic mutations as potential biomarker for immunotherapy in elder or TP53 mutated gastric cancer patients
Jun Yao1, Qing You1, Xin Zhang1
1Department of Gastrointestinal Surgery, Changzheng Hospital, Naval Medical University, Shanghai, China.
Abstract:
Immune checkpoint inhibitors (ICIs) improve overall survival in patients with advanced gastric cancer (GC). However, the molecular characterization of GC in ICIs responders is unclear. A total of 288 advanced GC patients were included in this study. Next-generation sequencing analysis was performed on tumor tissue and paired blood to screen for somatic mutants in 639 tumor-associated genes. We demonstrated that ARID1A, HER2/3/4, KMT2C/2D, LRP1B, PIK3CA, SPTA1, and TP53 mutations were significantly correlated with high tumor mutation burden (TMB) score, as well as HER2 amplification. For HER2 and PIK3CA mutations types, this relationship was statistically significant with age and TP53 mutation status, which was also found in the CDH1 gene. These results were confirmed by sequencing 873 GC cases in the cBioPortal database. PIK3CA mutations appear to be associated with longer survival in elderly population and TP53 mutant subtypes. For the first time, we found that GC patients ≥60 years old or with TP53 mutated type and PIK3CA mutations were associated with higher TMB and better ICI response. Building upon the age and TP53 mutation status, this study suggested a novel stratification approach to GC patients and explored the correlations between genetic somatic mutations and TMB score.
Insights
Immune checkpoint inhibitors (ICIs) benefit advanced gastric cancer (GC) patients. This study identifies specific gene mutations (PIK3CA, TP53) and age as predictors of better ICI response in GC.
Area of Science:
- Oncology
- Genetics
- Immunotherapy
Background:
- Immune checkpoint inhibitors (ICIs) enhance survival in advanced gastric cancer (GC).
- Molecular profiles of GC patients responding to ICIs remain largely undefined.
- Understanding genetic drivers of ICI response is crucial for personalized treatment strategies.
Purpose of the Study:
- To elucidate the molecular characteristics of advanced GC patients who respond to ICIs.
- To identify specific gene mutations and clinicopathological factors associated with high tumor mutation burden (TMB) and ICI efficacy.
- To propose a novel stratification approach for GC patients based on genetic profiles and age.
Main Methods:
- Next-generation sequencing of 639 tumor-associated genes in 288 advanced GC patients.
- Analysis of tumor tissue and paired blood for somatic mutations.
- Validation of findings using the cBioPortal database with 873 GC cases.
Main Results:
- Mutations in ARID1A, HER2/3/4, KMT2C/2D, LRP1B, PIK3CA, SPTA1, and TP53 correlated with high TMB and HER2 amplification.
- PIK3CA and TP53 mutations showed significant associations with age and ICI response.
- GC patients aged ≥60 years or with TP53/PIK3CA mutations exhibited higher TMB and better ICI response.
Conclusions:
- Specific genetic mutations (e.g., PIK3CA, TP53) and patient age are key determinants of ICI response in advanced GC.
- A novel stratification approach integrating age and TP53/PIK3CA mutation status can predict ICI efficacy.
- Further research into genetic markers can optimize immunotherapy selection for GC patients.
