Genomic analysis of oesophageal carcinoma (EC) identifies recurrent mutations in histone methyltransferases as a distinctive subset.

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.