Proteogenomic and Metabolomic Characterization of Human Glioblastoma.
Glioblastoma (GBM) is the most aggressive nervous system cancer. Understanding its molecular pathogenesis is crucial to improving diagnosis and treatment. Integrated analysis of genomic, proteomic, post-translational modification and metabolomic data on 99 treatment-naive GBMs provides insights to GBM biology. We identify key phosphorylation events (e.g., phosphorylated PTPN11 and PLCG1) as potential switches mediating oncogenic pathway activation, as well as potential targets for EGFR-, TP53-, and RB1-altered tumors. Immune subtypes with distinct immune cell types are discovered using bulk omics methodologies, validated by snRNA-seq, and correlated with specific expression and histone acetylation patterns. Histone H2B acetylation in classical-like and immune-low GBM is driven largely by BRDs, CREBBP, and EP300. Integrated metabolomic and proteomic data identify specific lipid distributions across subtypes and distinct global metabolic changes in IDH-mutated tumors. This work highlights biological relationships that could contribute to stratification of GBM patients for more effective treatment.
Wang LB, Karpova A, Gritsenko MA, Kyle JE, Cao S, Li Y, Rykunov D, Colaprico A, Rothstein JH, Hong R, Stathias V, Cornwell M, Petralia F, Wu Y, Reva B, Krug K, Pugliese P, Kawaler E, Olsen LK, Liang WW, Song X, Dou Y, Wendl MC, Caravan W, Liu W, Cui Zhou D, Ji J, Tsai CF, Petyuk VA, Moon J, Ma W, Chu RK, Weitz KK, Moore RJ, Monroe ME, Zhao R, Yang X, Yoo S, Krek A, Demopoulos A, Zhu H, Wyczalkowski MA, McMichael JF, Henderson BL, Lindgren CM, Boekweg H, Lu S, Baral J, Yao L, Stratton KG, Bramer LM, Zink E, Couvillion SP, Bloodsworth KJ, Satpathy S, Sieh W, Boca SM, Schürer S, Chen F, Wiznerowicz M, Ketchum KA, Boja ES, Kinsinger CR, Robles AI, Hiltke T, Thiagarajan M, Nesvizhskii AI, Zhang B, Mani DR, Ceccarelli M, Chen XS, Cottingham SL, Li QK, Kim AH, Fenyö D, Ruggles KV, Rodriguez H, Mesri M, Payne SH, Resnick AC, Wang P, Smith RD, Iavarone A, Chheda MG, Barnholtz-Sloan JS, Rodland KD, Liu T, Ding L; Clinical Proteomic Tumor Analysis Consortium. Proteogenomic and metabolomic characterization of human glioblastoma. Cancer Cell. 2021 Apr 12;39(4):509-528.e20. doi: 10.1016/j.ccell.2021.01.006. Epub 2021 Feb 11. PMID: 33577785; PMCID: PMC8044053.