Large-scale analysis of KMT2 mutations defines a distinctive molecular subset with treatment implication in gastric cancer

Jingyuan Wang, Joanne Xiu, Yasmine Baca, Francesca Battaglin, Hiroyuki Arai, Natsuko Kawanishi, Shivani Soni, Wu Zhang, Joshua Millstein, Bodour Salhia, Richard M. Goldberg, Philip A. Philip, Andreas Seeber, Jimmy J. Hwang, Anthony F. Shields, John L. Marshall, Igor Astsaturov, A. Craig Lockhart, Zoran Gatalica, W. Michael KornHeinz Josef Lenz

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4894-4905
Number of pages12
JournalOncogene
Volume40
Issue number30
DOIs
StatePublished - Jul 29 2021

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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