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KMT2C mutation as a predictor of immunotherapeutic efficacy in colorectal cancer
Chunhua Ni1, Xiaohong Wang2, Shaoping Liu3
1Department of Gastrointestinal Surgery, Nanjing Jiangning Hospital of Chinese Medicine, Nanjing, China.
Abstract:
Immunotherapy had shown good antitumor activity in a variety of solid tumors, but low benefit in CRC, so there was an urgent need to explore new biomarkers. We evaluated the role of KMT2C using publicly available data from the Cancer Genome Atlas (TCGA) and Memorial Sloan Kettering Cancer Center (MSKCC). In addition, further analysis was performed in an internal cohort. Moreover, the mutant profiles of KMT2C was analyzed in a large CRC cohort. The relationship between clinical pathologic features and KMT2C were analyzed with using the two-sided chi-squared test or the Fisher exact test. Clinicopathologic characteristics associated with overall survival using Cox regression and the Kaplan-Meier method. We found that KMT2C-mutated CRC patients in the immunotherapy cohort had significantly improved OS compared with KMT2C WT patients (P = 0.013). However, this phenomenon did not exist in non-immunotherapy cohort. Our cohort validated the value of KMT2C mutations in predicting better clinical outcomes, including ORR (P < 0.0001) and OS (P = 0.010). Meanwhile, KMT2C mutation was associated with higher tumor mutation burden, MSI score, higher levels of immune-associated T cells, neutrophil, and M1-type macrophages. Our study suggested that KMT2C mutation might be a potential positive predictor for CRC immunotherapy.
Insights
KMT2C mutations predict better outcomes in colorectal cancer (CRC) patients receiving immunotherapy. This finding highlights KMT2C as a potential biomarker for improving CRC treatment response.
Area of Science:
- Oncology
- Genetics
- Immunology
Background:
- Immunotherapy shows promise in solid tumors but limited benefit in colorectal cancer (CRC).
- There is an urgent need for novel biomarkers to predict immunotherapy response in CRC.
- KMT2C gene mutations are explored as potential predictive markers.
Purpose of the Study:
- To evaluate the role of KMT2C mutations in predicting clinical outcomes for colorectal cancer patients undergoing immunotherapy.
- To analyze the association between KMT2C mutation status and tumor immune microenvironment characteristics.
Main Methods:
- Utilized publicly available data from The Cancer Genome Atlas (TCGA) and Memorial Sloan Kettering Cancer Center (MSKCC).
- Performed analysis on an internal cohort and a large CRC cohort for KMT2C mutation profiles.
- Employed chi-squared test, Fisher exact test, Cox regression, and Kaplan-Meier methods for statistical analysis.
Main Results:
- KMT2C-mutated CRC patients in the immunotherapy cohort showed significantly improved overall survival (OS) compared to KMT2C wild-type (WT) patients (P=0.013).
- This survival benefit was not observed in the non-immunotherapy cohort.
- KMT2C mutations were validated to predict better objective response rate (ORR) (P<0.0001) and OS (P=0.010) in the internal cohort.
- KMT2C mutation correlated with higher tumor mutation burden, MSI score, and increased infiltration of immune cells like T cells, neutrophils, and M1 macrophages.
Conclusions:
- KMT2C mutation status is a significant predictor of improved clinical outcomes in CRC patients treated with immunotherapy.
- KMT2C mutations are associated with a more favorable tumor immune microenvironment, suggesting a role in enhancing immunotherapy efficacy.
- KMT2C may serve as a potential positive biomarker for predicting response to immunotherapy in colorectal cancer.
