Biological and prognostic relevance of epigenetic regulatory genes in high-grade gliomas (HGGs).
Authors: Aulakh Sonikpreet , Xiu Joanne , Brodskiy Pavel , Fonkem Ekokobe , Darabi Sourat , Demeure Michael J. , Sengupta Soma , Kesari Santosh , Ashley David M. , Sumrall Ashley Love , Glantz Michael J. , Spetzler David 
Published: June 2022

2019 Background: Gliomagenesis is regulated by dynamic epigenetic modifications of DNA methylation, deregulation of histones and alteration of the human Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complexes. These epigenetic genes are responsible for treatment resistance by inducing stemness of glioma cells and immune cells with in the tumor microenvironement (TME). We evaluated the key chromatin remodeling (CR) genes and their interactions with other regulatory genes that are of prognostic importance. Methods: 1856 HGGs underwent molecular profiling at Caris Life Sciences (Phoenix, AZ). Analyses included next-generation sequencing of DNA (592 Genes, NextSeq or WES, NovaSeq) and RNA (WTS, NovaSeq). Cell infiltration in the TME was estimated by quanTIseq. X2/Fisher’s-exact/Mann-Whitney U tests were used for comparison, and significance was determined as p-value adjusted for multiple comparison by the Benjamini-Hochberg method (q < 0.05). Overall survival (OS) was calculated from the start of temozolomide (TMZ) to last contact using insurance claims data. Results: In a cohort of 1856 HGGs, 181 (9.8%) displayed >=1 mutation of 19 CR genes considered, including mutations (mt) of histone methyltransferases (HM) comprising SETD2 (62, 3.4%), KMT2D (18, 1.0%), KMT2C (11, 0.6%); SWI/SNF complexes (SSNF) including ARID1A (32, 1.74%), ARID2 (15, 0.82%), SMARCA4 (14, 0.76%) and ARID1B (12, 0.66%); and others including ( DNMT3A, 0.94%, ASLXL1: 13, 0.98%). When compared to CR-WT, CR-mt HGGs showed higher prevalence of Tumor Mutational Burden-High (TMB-H) (23% vs. 1.3%), MSI-H/dMMR (13% vs. 0.2%), gLOH (9.5% vs 4.3%), and mts in IDH1/2 (29% vs. 14%), TP53 (55% vs. 36%), MSH6 (8.8% vs. 0.6%), and PIK3CA (18.8% vs. 8.3%) (all q<0.05). Investigation of CR-mt subgroups showed that SSNF mt had the highest MGMT-promoter methylation (68%) and IDH1/2 mt (46%), while HM and others showed similar prevalence. In IDH-WT and MSS HGGs, the CR association with TMB-H, MSH6, TP53 and PIK3CA persisted (q<0.05). When studying the immune profile, CR-mt HGGs showed significantly lower expression of immune-related genes including PD-L1 (Fold change: 0.76), PD-L2 (0.72), IDO1 (0.65), TIM3 (0.76) and CD86 (0.77) and colder TME as manifested by lower infiltrations of M2 (0.87) and higher Treg (1.27, all q<0.05); such effects were not observed in the subgroup of IDH WT/MSS tumors. Among TMZ-treated HGG tumors, CR mt was associated with improved OS (33 months vs 22m, HR: 0.713, 95% CI: 0.581-0.876, p =.001). In the IDH WT/MSS subgroup this effect was also observed (31.6m vs 19.2m, HR: 0.764, 95% CI: 0.59-0.99, p = 0.041). Conclusions: Nearly 10% of HGGs carry mts in CR genes. CR-mt HGGs possess significantly more favorable genetic alterations and colder TME compared to the CR-WT HGGs and showed better OS when treated with TMZ. Multivariate modeling and analysis of associations with specific targeted therapies is underway.