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

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.

• Authors: 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 Korn, Heinz-Josef Lenz
• Journal: Oncogene (Oncogene) Vol. 40 Issue 30 Pg. 4894-4905 (07 2021) ISSN: 1476-5594 [Electronic] England
• PMID: 34163031 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• Biomarkers, Tumor
• Isoenzymes
• Histone-Lysine N-Methyltransferase

Topics

• Aged
• Aged, 80 and over
• Biomarkers, Tumor
• DNA Mismatch Repair
• DNA Mutational Analysis
• Databases, Genetic
• Female
• Gene Frequency
• Histone-Lysine N-Methyltransferase (genetics, metabolism)
• Humans
• Isoenzymes (genetics)
• Kaplan-Meier Estimate
• Male
• Microsatellite Instability
• Middle Aged
• Mutation
• Neoplasm Grading
• Neoplasm Staging
• Prognosis
• Stomach Neoplasms (diagnosis, drug therapy, genetics, metabolism)
• Tumor Microenvironment