Abstract B032: Pancancer genomic analysis reveals histone H3K36 and H3K27 modifiers and readers as prognostic factors in patients with cancer


 Histone modifications are a crucial component of the epigenetic regulation of human transcriptome and cellular homeostasis. Among these modifications, lysine (K) methylation in various sites of histones is orchestrated by a complex network of histone writers - methyltransferases, and histone erasers - demethylases. Furthermore, the establishment of histone lysine methylation is recognized by a variety of adaptor proteins, also known as histone readers, and mediate their signaling importance through formation of other protein complexes, affecting a plethora of cellular functions such as transcription, RNA splicing, DNA-damage response and proliferation. Among other modifications, the Histone H3 Lysine 27 (K27) and Lysine 36 (K36) methylations have been implicated in a plethora of human diseases, with their misregulation to be prominent for human cancer and developmental defects. Cancer cells usually hijack these pathways through mutations and/or aberrant expression of these modifiers, promoting cancer growth and metastatic potential. Nevertheless, regardless of the major therapeutic potential of these pathways, a comprehensive pan-cancer analysis for the prevalence and impact of genomic alterations of Histone H3K27 and H3K36 methylation modifiers in human cancer has not been undergone yet. Here, we sought to identify the genomic alterations of these effectors through a pan-cancer analysis of Whole Exome Sequence data (WES) from The Cancer Genome Atlas (TCGA). To this extent, we analyzed 11,194 patients samples with 33 different types of human cancer, available through cbioportal.org, for genomic alterations in 32 histone H3K27 and H3K36 modifiers and readers. The most common genomic alterations were observed in KDM6B, BRPF1, KDM6A, SETD2 and NSD1 (5%, 5%, 4% and 4% respectively). Interestingly, the patient group with genomic alterations was significantly most likely to present with concurrent oncogenic alterations in TP53, PIK3CA, TERT, ARID1A and KMT2A, among other alterations. Furthermore, our analysis demonstrated that several of these alterations co-occur (p<0.0001). More importantly, clinical and survival analysis revealed poor overall survival in the pan-cancer group of patients with genomic alterations of these modifiers (HR = 1.14, p=0.031), demonstrating the oncogenic and prognostic importance of these mutations in human cancer. Collectively, our pan-cancer analysis implicates the histone H3K27 and H3K36 modifiers and erasers as a major oncogenic pathway and their alterations as an important driver for human cancer, and sets the stage for further pre-clinical and translational research on the potential therapeutic potential of this pathway.
 Citation Format: George Laliotis, Pauline Lin. Pancancer genomic analysis reveals histone H3K36 and H3K27 modifiers and readers as prognostic factors in patients with cancer. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B032.