Aim: Glioblastoma multiforme (GBM) carries a dismal prognosis. Integrated proteogenomic analysis was performed to understand GBM pathophysiology. Patients & methods: 17 patient samples were analyzed for driver mutations, oncogenes, major pathway alterations and molecular changes at gene and protein level. Clinical, treatment and survival data were collected. Results: Significantly mutated genes included TP53, EGFR, PIK3R1, PTEN, NF1, RET and STAG2. EGFR mutations noted included EGFRvIII-expression, EGFR- L816Q missense mutation-exon 21 and EGFR fusion (FGFR3-TACC3). TP53 mutations were noticed in COSMIC hot-spot driver gene and accompany IDH1 and ATRX mutations suggesting low- to high-grade glioma transformation. Proteomics showed higher (53%) EGFR expression than genomic expression (23%). MGMT methylation was present in two-thirds of cases. Conclusion: This study identifies a distinct biological process that may characterize each GBM differently. Proteogenomic data identify potential therapeutic targets of GBM.
e13521 Background: Glioblastoma (GBM) is an aggressive primary brain tumor carrying a dismal prognosis. Understanding molecular architecture of GBM is crucial for development of successful therapies against it. In this study, we performed an integrated proteogenomic analysis to determine a more comprehensive understanding of GBM phenotype. Methods: We performed quantitative proteomics and integrative genomic analysis based on The Cancer Genome Atlas (TCGA) datasets of GBM on 17 consecutive GBM patients. We collected information on driver mutations, oncogenes, major pathway alterations, mutation burden and molecular changes at both gene and protein level as well as clinical, treatment and survival data for the entire group. Results: Significantly mutated genes include TP53, EGFR, PIK3R1, PTEN, NF1, RET and STAG2. EGFR alterations by DNA amplification with multiple mutation allele frequencies were seen in 5(29.4%) patients including EGFRvIII expression, L816Q EGFR missense mutation on exon 21 and EGFR fusion (FGFR3-TACC3); all three are potential therapeutic targets of novel agents including EGFRvIII-specific dendritic cell vaccine, EGFR inhibitors and FGFR inhibitors. TP53 mutation was noticed in 30% of patients. TP53 Mutations were noticed in COSMIC hot spot driver gene and accompany IDH1 and ATRX mutations suggesting transformation from low to high-grade glioma. Only 1 patient had a high mutation burden and expired 17 months after initial diagnosis. In contrast, proteomics showed significantly high(n = 9,53%) EGFR expression. 75% of GBMs were MGMT methylated, a predictive marker of response to temozolomide. Twelve of the 17 patients are still alive; median overall survival was 16.5 months. Lowest survival observed was 5 months. Conclusions: This study identifies a distinct biological process that may characterize each glioblastoma differently. Proteogenomic data effectively recognizes potential therapeutic targets of GBM such as Exon 21 missense mutation, previously reported in lung adenocarcinoma with promising response to anti-EGFR antibodies. Incorporation of Whole Genome Sequencing into clinical practice will allow identification of new treatment options for GBM.
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