Characterizing the Evolving Genomic Landscape of Histone and Partner Gene Mutations in Pediatric High-Grade Gliomas
Open Access DepositedCentral nervous system (CNS) tumors are the leading cause of childhood cancer-related mortality. Pediatric high-grade gliomas (pHGGs) are among the deadliest of CNS cancers and frequently harbor somatic mutations altering histone H3-encoding genes. Over 80% of midline pHGGs harbor a lysine-27-to-methionine conversion (H3K27M). H3K27M most often arises in the gene H3-3A encoding histone variant H3.3 (60% of cases), and less often affects H3.1/H3.2-encoding genes (20%). In contrast, up to 25% of hemispheric pHGGs harbor a glycine-34-to-arginine/valine (H3G34R/V) mutation arising in H3-3A. Given that these mutations alter regulatory N-terminal tail residues of the core histone H3 protein, they result in drastic biological changes including global genome hypomethylation and genomic instability. However, there has yet to be a comprehensive interrogation of the full landscape of histone gene alterations in pHGGs. Moreover, given that histone mutations lead to increased genomic instability, there is a need to longitudinally monitor the evolving pHGG genome during therapy. Emerging data point to a growing role for mutations altering both core histone and linker histone proteins in several cancers. However, the prevalence and biological consequences of novel (non-H3K27/G34) histone mutations in pHGGs remain unknown. To address this knowledge gap, we generated a comprehensive pan-cancer histone mutational atlas to define the histone mutation landscape of pHGGs and place them in the context of other pediatric and adult cancers. Our analyses revealed that a subset of pHGGs harbor previously unknown mutations altering core and linker histone proteins. Moreover, we delineated associations between histone mutation subtypes, oncogenic transcriptional programs, and drug response profiles, revealing the biological and clinical relevance of these mutations. Our findings contributed to a more complete understanding of the underlying genetic fingerprint of pHGGs, revealing novel and biologically relevant histone alterations. Histone gene mutations lead to epigenetic perturbation and genomic instability, thereby introducing the need to longitudinally monitor the evolving pHGG genome to evaluate changes in tumor mutation burden. H3 mutations (H3K27M, G34R/V) co-occur with certain partner gene mutations including TP53 and PDGFRA; importantly, the pattern of partner mutations exhibits inter- and intra-tumoral heterogeneity and evolves during spatiotemporal tumor spread. Indeed, rare cases of paired upfront and progression tissue biopsies have revealed the expansion of distinct sub-clonal partner mutations at disease progression when compared to initial diagnostic biopsy, which can influence tumor response/resistance to therapy. However, the process of pHGG genomic evolution remains masked by the delicate neuroanatomical location and infeasibility of repeated surgical tissue biopsies for most patients. To address this problem, we developed and employed minimally invasive approaches to profile histone and partner gene mutations using patient liquid biopsies. Our results provided an opportunity for comprehensive mutation detection and longitudinal monitoring of pHGG genomic heterogeneity and evolution, without requiring invasive tissue biopsies. Collectively, our findings defined the genomic landscape of histone gene alterations in pHGGs, revealing novel mutations in a subset of patients. Moreover, we provided an innovative, minimally invasive approach to comprehensively profile histone and partner gene mutations, and to monitor tumor genomic heterogeneity and evolution during therapy. These findings, together with recent progress in the field of pHGG research, advanced our understanding of, and ability to surveil, the evolving tumor genomic landscape in children diagnosed with pHGG and other CNS cancers.
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Dissertation_ERB_Final__-_Erin_Bonner.pdf | 2022-08-22 | Open Access |
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