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Wang J , Xiu J , Baca Y , Battaglin F , Arai H , Kawanishi N , Soni S , Zhang W , Millstein J , Salhia B , Goldberg RM , Philip PA , Seeber A , Hwang JJ , Shields AF , Marshall JL , Astsaturov I , Craig Lockhart A , Gatalica Z , Michael Korn W , Lenz HJ
Large-scale analysis of KMT2 mutations defines a distinctive molecular subset with treatment implication in gastric cancer
Oncogene. 2021 Jun 23;40(30) :4894-4905
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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.
1476-5594 Wang, Jingyuan Xiu, Joanne Baca, Yasmine Battaglin, Francesca Arai, Hiroyuki Orcid: 0000-0002-1886-7070 Kawanishi, Natsuko Soni, Shivani Zhang, Wu Millstein, Joshua Salhia, Bodour Orcid: 0000-0003-3843-3621 Goldberg, Richard M Philip, Philip A Seeber, Andreas Orcid: 0000-0001-8529-7824 Hwang, Jimmy J Shields, Anthony F Marshall, John L Astsaturov, Igor Orcid: 0000-0002-8613-1890 Craig Lockhart, A Gatalica, Zoran Michael Korn, W Lenz, Heinz-Josef Orcid: 0000-0003-2178-9568 Journal Article England Oncogene. 2021 Jun 23. doi: 10.1038/s41388-021-01840-3.