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Updated: Nov 1, 2025
Comparative Lesions Analysis Through a Targeted Sequencing Approach
Published on: November 5, 2019
Large-scale analysis of KMT2 mutations defines a distinctive molecular subset with treatment implication in gastric
Jingyuan Wang1,2, Joanne Xiu3, Yasmine Baca3
1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China.
Abstract:
Frequent mutations of genes in the histone-lysine N-methyltransferase 2 (KMT2) family members were identified in gastric cancers (GCs). Understanding how gene mutations of KMT2 family affect cancer progression and tumor immune microenvironment may provide new treatment strategies. A total of 1245 GCs were analyzed using next-generation sequencing, whole transcriptome sequencing, immunohistochemistry (Caris Life Sciences, Phoenix, AZ). The overall mutation rate of genes in the KMT2 family was 10.6%. Compared to KMT2-wild-type GCs, genes involved in epigenetic modification, receptor tyrosine kinases/MAPK/PI3K, and DNA damage repair (DDR) pathways had higher mutation rates in KMT2-mutant GCs (p < 0.05). Significantly higher rates of high tumor mutational burden, microsatellite instability-high/mismatch-repair deficiency (dMMR), and PD-L1 positivity were observed in KMT2-mutant GCs (p < 0.01), compared to KMT2-wild-type GCs. The association between PD-L1 positivity and KMT2 mutations remained significant in the proficient-MMR and microsatellite stable subgroup. Based on transcriptome data from the TCGA, cell cycle, metabolism, and interferon-α/β response pathways were significantly upregulated in KMT2-mutant GCs than in KMT2-wild-type GCs. Patients with KMT2 mutation treated with immune checkpoint inhibitors had longer median overall survival compared to KMT2-wild-type patients with metastatic solid tumors (35 vs. 16 months, HR = 0.73, 95% CI: 0.62-0.87, p = 0.0003). In conclusion, this is the largest study to investigate the distinct molecular features between KMT2-mutant and KMT2-wild-type GCs to date. Our data indicate that GC patients with KMT2 mutations may benefit from ICIs and drugs targeting DDR, MAPK/PI3K, metabolism, and cell cycle pathways.
Insights
Frequent mutations in histone-lysine N-methyltransferase 2 (KMT2) genes are common in gastric cancer (GC). KMT2-mutant GCs exhibit distinct molecular features, including higher tumor mutational burden and PD-L1 positivity, suggesting potential benefits from immune checkpoint inhibitors.
Area of Science:
- Oncology
- Cancer Genomics
- Tumor Microenvironment
Background:
- Frequent mutations in histone-lysine N-methyltransferase 2 (KMT2) family genes are observed in gastric cancers (GCs).
- Understanding the impact of KMT2 mutations on GC progression and the tumor immune microenvironment is crucial for developing novel therapeutic strategies.
Purpose of the Study:
- To investigate the distinct molecular features of KMT2-mutant versus KMT2-wild-type gastric cancers.
- To explore the relationship between KMT2 mutations and the tumor immune microenvironment.
- To assess the potential therapeutic implications of KMT2 mutations in GC patients.
Main Methods:
- Analysis of 1245 GCs using next-generation sequencing, whole transcriptome sequencing, and immunohistochemistry.
- Comparison of molecular features, including pathway mutations, tumor mutational burden, microsatellite instability, mismatch-repair deficiency (dMMR), and PD-L1 expression, between KMT2-mutant and KMT2-wild-type GCs.
- Evaluation of survival outcomes in patients treated with immune checkpoint inhibitors (ICIs).
Main Results:
- KMT2 family gene mutations occurred in 10.6% of GCs.
- KMT2-mutant GCs showed higher mutation rates in epigenetic modification, receptor tyrosine kinases/MAPK/PI3K, and DNA damage repair (DDR) pathways.
- Significantly higher rates of high tumor mutational burden, microsatellite instability-high/dMMR, and PD-L1 positivity were observed in KMT2-mutant GCs.
- KMT2-mutant GCs exhibited upregulated cell cycle, metabolism, and interferon-α/β response pathways.
- Patients with KMT2 mutations treated with ICIs had longer median overall survival (35 months) compared to KMT2-wild-type patients (16 months).
Conclusions:
- This study represents the largest investigation into the molecular differences between KMT2-mutant and KMT2-wild-type GCs.
- GC patients with KMT2 mutations display distinct molecular profiles, including enhanced immune microenvironment markers.
- KMT2-mutant GCs may respond favorably to immune checkpoint inhibitors and targeted therapies for DDR, MAPK/PI3K, metabolism, and cell cycle pathways.
