Epigenomic glioma subtype evaluation across 31 tumor types

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Conference Proceeding

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BACKGROUND: A recent molecular low and high grade glioma (G) epigenomic profiling has uncovered clinically relevant subtypes that refined the existent glioma classification (based on IDH and codeletion status) into seven discrete groups with distinct clinicopathological and prognostic outcomes. IDH-mutants gliomas were further classified in G-CIMP-low and -high or codel and IDH-wildtype (wt) in classic-like, mesenchymal-like, and IDH-wt-K3 (LGm6-GBM, and PA-like subgroups). Epigenetic signatures defined prognostic outcome among gliomas. We hypothesized that the glioma methylome-based signatures may also classify other tumors into discrete subgroups with prognostic relevance. METHODS: Utilizing the Random Forest method, we analyzed the 450K-platform-based methylome of 7,656 samples across 31 primary tumor types (pan-cancer) and classified those tumors according to the glioma methylome-based signatures. RESULTS: The majority of cancer samples fell into the glioma IDH-wtlike group (98.5%). Within it, glioma-IDH-wt-K3-like subtype (n=3147) had a significant better overall survival (OS) than glioma-mesenchymallike (n=3670) and glioma-classic-like (n=658) subgroups (p=2e-16), resembling the behavior of the correspondent glioma subtypes. In contrast to gliomas, in which G-CIMP-low subtype had poorer OS than G-CIMP-high and codels, no significant differences in OS were found among the IDHmutant subtypes. In the IDH-mut-like pan-cancer group, G-CIMP-high/ low subtypes and glioma-codel-like presented none or only 3% IDH mutations, respectively. CONCLUSION: The pan-cancer glioma-methylome signatures revealed that most of human tumors fall into the glioma IDH-wt subtype with similar OS pattern as in gliomas. Among the IDH-mutantlike pan-cancer subtype, the OS were similar among subgroups. IDH was not mutated in the CIMP-like cancer group, suggesting that although these tumors resemble the G-CIMP molecular profile, the molecular mechanisms that may drive the epigenetic phenotype and OS in those tumors are yet to be determined.




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