Genomic analysis of oesophageal carcinoma (EC) to identify recurrent mutations in histone methyltransferases as a distinctive subset.
Year: 2024
Type: conference-abstract
Abstract: 379 Background: Histone-lysine N-methyltransferase 2 (KMT2) family proteins methylate lysine 4 on the histone H3 tail at important regulatory regions in the genome and thereby impart crucial functions through modulating chromatin structures and DNA accessibility, which is associated with tumorigenesis and immune tolerance, indicating its possible correlation with the efficacy of immunotherapy. Recurrent mutations of KMT2 have been identified in EC, but data addressing the molecular features of KMT2 mutated (MT) EC are lacking. We aimed to understand the molecular profile of KMT2 -MT EC. Methods: A total of 787 oesophageal carcinoma [adenocarcinoma (EAC), N=604; squamous cell carcinoma (ESCC), N=183] were analyzed using next-generation sequencing (NGS) and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous mutations, and mismatch repair deficiency (dMMR)/microsatellite instability-high (MSI-H) status was evaluated by a combination of IHC, Fragment analysis and NGS. Results: The mutation spectrum of KMT2A/C/D was significantly different between ESCC and EAC ( KMT2A, 2.7% vs. 1.2%; KMT2C, 3.8% vs. 1.2%; KMT2D, 14.2% vs. 2.0%, P <0.05). KMT2-MT EAC tumors showed significantly higher mutation rates in CIC (13% vs 1.1%), NF1 (12.5% vs 2.2%), FBXW7 (12% vs 3.4%), ATM (11.5% vs 2.6%) and BRCA1 (11.5% vs 1%, all q<0.05), compared to KMT2-WT tumors. However, in ESCC there were no significant differences in gene mutations between the KMT2-MT and WT groups. Significantly higher rates of dMMR/MSI-H (19.2% vs 1.0% in EAC, 5.4% vs. 0% in ESCC, both p<0.01) were seen in both KMT2-MT ESCC and EAC, compared to KMT2-WT cohorts, respectively. TMB was significantly higher in both KMT2-MT ESCC (median: 10 vs 8.6 mut/Mb, P=0.042) and EAC (23.9 vs 8.0 mut/Mb, P<0.0001), compared to KMT2-WT cohorts, respectively. A numerically longer immune-related overall survival was observed in KMT2 -MT EC patients, compared to KMT2 -WT EC patients (9.05 vs 6.98 months, HR=0.744, 95%CI: 0.52-1.07, P =0.11). Conclusions: This is the largest study to investigate the distinct genomic landscapes between KMT2 -MT and WT EC to date. Our data showed the KMT2 -MT EC has a distinctive genetic profile, indicated by higher TMB, and higher frequency of dMMR/MSI-H and gene mutations involved in DDR and epigenetic regulation. Understanding these molecular characteristics may be informative in the development of effective treatment strategies in KMT2 -MT EC.
Source: Journal of Clinical Oncology
Authors: Jingyuan Wang, Joanne Xiu, Matthew James Oberley, Francesca Battaglin, Hiroyuki Arai, Shivani Soni, Wu Zhang, Richard M. Goldberg, Anthony F. Shields, Axel Grothey, Jimmy J. Hwang, John Marshall, Igor A. Astsaturov, Benjamin Adam Weinberg, Emil Lou, Michael J. Hall, Rachna T. Shroff, Moh'd M. Khushman, Davendra Sohal, Heinz-Josef Lenz
Institutions: Fudan University, Zhongshan Hospital, Caris Life Sciences (United States), University of Southern California, USC Norris Comprehensive Cancer Center, West Virginia University, The Barbara Ann Karmanos Cancer Institute, West Cancer Center, Levine Cancer Institute, Georgetown University, Georgetown University Medical Center, Georgetown Lombardi Comprehensive Cancer Center, Fox Chase Cancer Center, University of Minnesota, University of Arizona Cancer Center, Washington University in St. Louis, University of Cincinnati, University of Cincinnati Medical Center
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4391094620