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Genome-Wide Analysis of DNA Methylation in Gastrointestinal Cancer
Published on: September 18, 2020
Genomic analysis of oesophageal carcinoma (EC) identifies recurrent mutations in histone methyltransferases as a
Jingyuan Wang1,2,3, Joanne Xiu4, Francesca Battaglin2
1Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.
Abstract:
Histone-lysine N-methyltransferase 2 (KMT2) family proteins methylate lysine 4 on the histone H3 tail at important regulatory regions in the genome and thereby impart crucial functions through modulating chromatin structures and DNA accessibility. We aimed to identify the molecular profile of KMT2-MT oesophageal cancer (EC) and associations with patient outcomes. In our study, KMT2 mutations were significantly associated with longer immunotherapy-related overall survival (OS) in the esophageal adenocarcinoma (EA) (21.42 vs 13.42 months, HR = 0.66, 95% CI: 0.50-0.88, P = 0.004), but not in the esophageal squamous cell carcinoma (ESCC). KMT2 mutations were significantly associated with microsatellite instability-high and higher tumor mutation burden in both EA and ESCC. KMT2-MT EA showed significantly higher mutation rates in CIC (13% vs 1.1%), NF1 (12.5% vs 2.2%), FBXW7 (12% vs 3.4%), ATM (11.5% vs 2.6%) and BRCA1 (11.5% vs 1%, all q < 0.05), compared to KMT2-wildtype (WT) tumors. Meanwhile, no significant mutational differences were observed between KMT2-MT and WT ESCC. Fat digestion and absorption, cholesterol metabolism and the infiltration of activated B cells were significantly enriched in KMT2-MT EA compared to KMT2-WT EA, but these results were not observed in the ESCC. This is the largest study to investigate the distinct molecular landscapes in KMT2-MT EC, characterized by higher tumor mutational burden, an increased frequency of microsatellite instability-high, and gene mutations involved in DNA damage repair and epigenetic regulation.
Insights
Histone-lysine N-methyltransferase 2 (KMT2) mutations are linked to improved immunotherapy survival in esophageal adenocarcinoma. These KMT2 mutations also correlate with higher tumor mutation burden and microsatellite instability in both esophageal cancer subtypes.
Area of Science:
- Genomics
- Cancer Biology
- Epigenetics
Background:
- Histone-lysine N-methyltransferase 2 (KMT2) proteins regulate chromatin structure and DNA accessibility.
- KMT2 family proteins are crucial for cellular functions via histone methylation.
- Understanding KMT2's role in esophageal cancer (EC) is vital for targeted therapies.
Purpose of the Study:
- To define the molecular profile of KMT2-mutated (KMT2-MT) esophageal cancer.
- To investigate the association between KMT2 mutations and patient outcomes.
- To explore differences in molecular landscapes between KMT2-MT and KMT2-wildtype (WT) EC.
Main Methods:
- Analysis of KMT2 mutation status in a large cohort of esophageal cancer patients.
- Comparison of overall survival (OS) between KMT2-MT and KMT2-WT groups.
- Whole-exome sequencing to identify co-occurring mutations and molecular pathways.
Main Results:
- KMT2 mutations correlated with longer immunotherapy-related OS in esophageal adenocarcinoma (EA), but not ESCC.
- KMT2 mutations were associated with microsatellite instability-high and increased tumor mutation burden in both EA and ESCC.
- KMT2-MT EA exhibited higher mutation rates in genes like CIC, NF1, FBXW7, ATM, and BRCA1, and enriched pathways in fat digestion and B cell infiltration.
Conclusions:
- KMT2 mutations characterize a distinct molecular subtype of EC with higher tumor mutational burden and microsatellite instability.
- KMT2-MT EA shows unique genomic alterations and pathway enrichment, suggesting different therapeutic vulnerabilities.
- KMT2 mutation status may serve as a predictive biomarker for immunotherapy response in EA.
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