OMIC-09. MAPPING THE HISTONE MUTATIONAL LANDSCAPE ACROSS ADULT AND PEDIATRIC CANCER GENOMES UNCOVERS NOVEL SOMATIC MUTATIONS IN PEDIATRIC HIGH-GRADE GLIOMAS

Abstract

There is a growing role for mutations affecting histone linker and histone core-encoding genes across several adult and pediatric cancers. However, the extent to which somatic histone mutations may bridge across different cancers as common tumorigenic events – particularly in the context of pediatric CNS tumors – remains unclear. To address this knowledge gap, we set out to define a comprehensive pan-cancer landscape of somatic histone mutations. We first queried the ICGC PCAWG and TCGA Pan-Cancer Atlas representing >12,500 adult and pediatric cancer patients. We found lymphomas to be most enriched for histone mutations (50–75%) and, in particular, for mutations in linker histones (HIST1H1B-E), yet also in specific core histone genes (eg, HIST2H2BE). Moreover, we observed a significant enrichment of histone mutations in adult high-grade vs low-grade gliomas (10% vs 6%, P<0.05, n=922 patients). Interrogation of whole genome data from 800 pediatric CNS tumor genomes (PBTA/OpenDIPG), identified novel (non-H3K27/non-H3G34) somatic histone mutations in 5–10% of subjects, including pediatric high-grade gliomas (pHGGs) and diffuse midline gliomas (DMGs). We found an overlapping set of histone genes to be recurrently mutated in non-CNS cancers and pediatric CNS tumors alike (eg, HIST1H1B/C/E). Notably, the only pediatric primary CNS lymphoma patient also harbored a histone linker alteration (HIST1H1B), similar to adult non-CNS lymphoma patients. We validated novel somatic histone mutations in DMGs by Sanger sequencing. Ongoing studies include in vitro assessment of the impact of these mutations on cell proliferation, chromatin accessibility, histone spacing, and gene expression. In addition, we will further assess associations with clinical outcome, age, and tumor subtypes. Collectively, oncohistone vulnerabilities were identified and defined as histone gene families recurrently mutated across all cancer types. Our analyses of adult and pediatric cancer genomes have uncovered previously unknown mutations affecting histone linker and core proteins, which may play a yet-undefined role in tumor etiology.