KMT2A/C mutations function as a potential predictive biomarker for immunotherapy in solid tumors
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LETTER TO THE EDITOR
Open Access
KMT2A/C mutations function as a potential predictive biomarker for immunotherapy in solid tumors Rui Zhang1†, Hao-Xiang Wu2†, Ming Xu1† and Xiaoyan Xie1*
Abstract Epigenetic factors play important roles in tumor immunology. Histone-lysine N-methyltransferase 2 (KMT2) family genes exert histone H3 methylation, but its role in immunotherapy remains unclear. Our study is the first to investigate the correlation between KMT2 gene mutations and the clinical benefit of immune checkpoint inhibitors (ICI) treatment. We firstly collected a primary ICI-treated cohort (n = 546) and found that patients with KMT2A/C mutations yielded better prognosis in terms of progression-free survival (PFS, Hazard ratio [HR] = 0.66, P = 0.002), objective response rate (ORR, 40.9% vs 20.3%, P < 0.001), durable clinical benefit (DCB, 48.3% vs 29.8%, P = 0.001) and overall survival (OS, HR = 0.70, P = 0.033). Furthermore, we validated the predictive potential of KMT2A/C mutations in an expanded ICI-treated cohort (n = 1395). KMT2A/C-mutant patients achieved better OS compared with KMT2A/C-wildtype patients (HR = 0.68, P = 0.003); and the survival advantages appeared in the majority of cancer subtypes. Our study suggests that KMT2A/C mutations function as a novel and potential predictive biomarker for ICI treatment in multiple solid tumors and the underlying mechanism is worth investigating. Keywords: Biomarker, Immune checkpoint inhibitors, KMT2A/C, Pan-cancer analysis To the Editor, Recent years have witnessed the great success of immune checkpoint inhibitors (ICIs) in treating multiple advanced tumors [1]. However, clinical response of ICIs varies and identification of predictive biomarkers is still in urgent demand. Growing evidence suggests that epigenetic factors play important roles in immuno-oncology [2, 3]. For example, the mutation in DNA demethylase TET1 predicted higher response rate in ICI-treated patients [4], and DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi) showed promising potentials to augment the efficacy of ICIs [5, 6]. * Correspondence: [email protected] † Rui Zhang, Hao-Xiang Wu and Ming Xu contributed equally to this work. 1 Department of Medical Ultrasound, Division of Interventional Ultrasound, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan 2nd Road, Guangzhou 510080, China Full list of author information is available at the end of the article
The KMT2 family genes, one of the important epigenetic regulator genes, were initially recognized in mixedlineage leukemia (MLL) caused by the rearrangement of KMT2A on chromosome 11q23 [7, 8]. Recent exomesequencing studies revealed that KMT2 genes were among the most frequently mutated genes in various types of human cancers [9]. The KMT2 proteins, namely KMT2A, KMT2B, KMT2C and KMT2D, function as methylating histone H3 on lysine 4 (H3K4) to promote genome accessibility and transcription, but its role in immunotherapy remains unclear. Herein, we investigated the correlation
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