دورية
Large-scale analysis of KMT2mutations defines a distinctive molecular subset with treatment implication in gastric cancer
| العنوان: | Large-scale analysis of KMT2mutations defines a distinctive molecular subset with treatment implication in gastric cancer |
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| المؤلفون: | Wang, Jingyuan, Xiu, Joanne, Baca, Yasmine, Battaglin, Francesca, Arai, Hiroyuki, Kawanishi, Natsuko, Soni, Shivani, Zhang, Wu, Millstein, Joshua, Salhia, Bodour, Goldberg, Richard M., Philip, Philip A., Seeber, Andreas, Hwang, Jimmy J., Shields, Anthony F., Marshall, John L., Astsaturov, Igor, Craig Lockhart, A., Gatalica, Zoran, Michael Korn, W., Lenz, Heinz-Josef |
| المصدر: | Oncogene; July 2021, Vol. 40 Issue: 30 p4894-4905, 12p |
| مستخلص: | 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 KMT2family 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 KMT2mutations 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 KMT2mutation 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 KMT2mutations may benefit from ICIs and drugs targeting DDR, MAPK/PI3K, metabolism, and cell cycle pathways. |
| قاعدة البيانات: | Supplemental Index |
| تدمد: | 09509232 14765594 |
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| DOI: | 10.1038/s41388-021-01840-3 |