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<p>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, <i>KMT2</i> 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, <i>P</i> = 0.004), but not in the esophageal squamous cell carcinoma (ESCC). <i>KMT2</i> mutations were significantly associated with microsatellite instability-high and higher tumor mutation burden in both EA and ESCC. <i>KMT2</i>-MT EA showed significantly higher mutation rates in <i>CIC</i> (13% vs 1.1%), <i>NF1</i> (12.5% vs 2.2%), <i>FBXW7</i> (12% vs 3.4%), <i>ATM</i> (11.5% vs 2.6%) and <i>BRCA1</i> (11.5% vs 1%, all q &lt; 0.05), compared to <i>KMT2</i>-wildtype (WT) tumors. Meanwhile, no significant mutational differences were observed between <i>KMT2</i>-MT and WT ESCC. Fat digestion and absorption, cholesterol metabolism and the infiltration of activated B cells were significantly enriched in <i>KMT2</i>-MT EA compared to <i>KMT2</i>-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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月11日

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  • Jingyuan Wang,
  • Joanne Xiu,
  • Francesca Battaglin,
  • Hiroyuki Arai,
  • Shivani Soni,
  • Wu Zhang,
  • Richard M. Goldberg,
  • Anthony F. Shields,
  • Axel Grothey,
  • Jimmy J. Hwang,
  • John L. Marshall,
  • Igor Astaturov,
  • Benjamin A. Weinberg,
  • Emil Lou,
  • Michael Hall,
  • Rachna T. Shroff,
  • Moh’d Khushman,
  • Mohamed E. Salem,
  • Davendra P. S. Sohal,
  • Aaron J. Scott,
  • Matt Oberley,
  • Tianshu Liu,
  • Lin Shen,
  • Heinz-Josef Lenz

摘要

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.