Correlation of KMT2 family mutations with molecular characteristics and prognosis in colorectal cancer.

Abstract

Lysine methyltransferase 2 (KMT2) family proteins methylate lysine 4 on histone H3 (H3K4) to promote genome accessibility and transcription. Dysregulation or mutation of KMT2 family have been observed frequently in various types of human cancers. Colorectal cancer is the third most common cancer worldwide. However, few studies have evaluated the role of KMT2 family mutations in colorectal cancer. The present study aimed to explore the impact of KMT2 family mutations on clinicopathological, molecular characteristics and prognosis in colorectal cancer. A total of 316 colorectal cancer patients were enrolled; tumor tissue and matched peripheral blood samples were collected and subjected to targeted sequencing with a panel of 1021 cancer-related genes. The association of clinical pathological features and molecular characteristics in patients were then analyzed. The cBioPortal dataset was used for investigating the KMT2 family mutations data and their correlation with clinical outcomes. The overall mutation frequencies of KMT2A-D were 9.5%, 0.5%, 13%, and 13%, respectively, which were more often present at right-sided primary and earlier stage tumors. KMT2A-D mutations are associated with enhanced genomic instability, including a higher level of microsatellite instability (MSI-H) and tumor mutational burden (TMB-H). In addition, our results highlight the co-occurring gene mutations within the Wnt signaling, ERBB2/4, TGF-β superfamily pathway, and PI-3-kinase pathway in KMT2-mutant colorectal cancer. KMT2 family mutations were predictive biomarker for better overall survival in metastatic colorectal cancer. Collectively, we identified that KMT2 family mutations were correlated with higher-TMB and higher-MSI, thus resulting in a better outcome for colorectal cancer patients.