Mutation Characteristics Of Histone Modification Related Genes In Cholangiocarcinoma.

Abstract Background and objective: Histone modification, as an important part of epigenetics researches, can cause tumorigenesis and development by changing chromatin status and regulating gene expression. Histone deacetylase (HDAC) inhibitors have made great progress as new drugs, and its mechanism is related to the mutation of HDAC family genes. However, mutations of other related genes lacked reports. Here, we analyzed the mutation characteristics of 13 histone related genes in patients with cholangiocarcinom. Methods: 380 cholangiocarcinom patients were enrolled. Next generation sequencing targeting 450 cancer genes was performed in OrigiMed. Disease-free survival (DFS) curve after operation was drawn with Kaplan-Meier and compared with Log-rank. Fisher's exact test was adapted to perform other statistical analysis. Results: 153 mutations were occurred in 13 histone modification related genes (HDAC1, HDAC7, HDAC9, KMT2A, KMT2B, KMT2C, KMT2D, KMT2E, KMT5A, KMT5B, EZH2, EP300 and CREBBP), and 66.7% (102/153) was substitution/indel, 31.4% (48/153) truncation and 2.0% (3/153) rearrangement. According to the mutation, patients were divided into histone gene wild type (WT) group and histone gene mutation type (MUT) group, patients with at least one mutation in 13 genes. Co-mutation analysis of 450 genes revealed that KTM2D and KTM6A tended to co-mutate with other genes, including FAT4, ATM, BRAF and ERBB3. KTM2C and KRAS mutation were mutually exclusive (P<0.01). 98 patients (25.8%) had at least one histone modification related mutation; Among them, KTM2C was the highest (10.5%, 40/380), followed by KTM2D (7.9%, 30/380), CREBBP (3.9%, 15/380), EP300 (3.4%, 13/380) , KTM2A (3.4%, 13/380) and HDAC9 (2.6%, 10/380). Furthermore, compared with WT group, patients in MUT group had a short DFS time after operation (mDFS: 7 vs 11.15 months, P=0.0139). Besides, the TMB had no significant difference between two groups, as well as the PD-L1 expression and microsatellite status. Conclusion: We firstly exhibited 13 histone related mutations in Chinese patients with cholangiocarcinoma. Mutations of histone modification related genes suggested poor outcomes of cholangiocarcinom. Citation Format: Yunfeng Li, Huanwei Chen, Zanmei Xu, Libo Yao, Junying Li, Chengzhi Cai, Dong You. Mutation characteristics of histone modification related genes in cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2664.