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The glioblastoma multiforme proteomeIntracranial tumors comprise approximately 2% of all adult cancers but form a larger fraction within the group of childhood tumors. Gliomas are tumors with an estimated origin from glial cells, accounting for approximately 80% of all malignant intracranial tumors. Gliomas are classified according to cell type of origin, differentiation and, malignancy grade. Gliomas include astrocytoma, oligodendrocytoma, and ependymoma, and are classified according to cell type of origin, differentiation and malignancy grade. Survival time after diagnosis with glioma varies significantly depending on grade. The prognosis for high-grade gliomas is poor due to limited possibilities of curative treatment. The most common form of glioma is astrocytoma, representing approximately 50% of all gliomas. Grade IV astrocytoma, also known as glioblastoma or glioblastoma multiforme (GBM) is the most common and aggressive glioma with a very poor 5-year survival (less than 5%). There is currently no cure for GBM, but it is normally treated with surgery followed by chemotherapy and radiotherapy to increase the length of survival. Here, we explore the GBM proteome using TCGA transcriptomics data and antibody-based protein data. 2018 genes are suggested as prognostic based on transcriptomics data from 141 patients; 935 genes are associated with unfavorable prognosis and 1088 genes are associated with favorable prognosis. TCGA data analysisIn this metadata study, we focused on the GBM data available from TCGA. The transcriptomics data was available from 141 patients; 48 female and 93 male, 29 were still alive and 112 patients deceased at the time of data collection. Information on stage distribution is missing. Unfavorable prognostic genes in GBMFor unfavorable genes, higher relative expression levels at diagnosis give significantly lower overall survival for the patients. There are 935 genes associated with an unfavorable prognosis in GBM, among these potential prognostic genes there are 57 genes that were validated in a separate study. In Table 1, the top 20 most significant genes related to an unfavorable prognosis are listed. CTSB is a gene associated with an unfavorable prognosis in GBM in two separate independent cohorts. The best separation is achieved by an expression cutoff at 301 TPM which divides the patients into two groups with 0% 3-year survival for patients with high expression versus 14% for patients with low expression, p-value: 1.85e-4. The TCGA data analysis was validated in a separate study with the p-value: 8.90e-4. Immunohistochemical staining using an antibody targeting CTSB (HPA048998) shows a differential expression pattern in glioma samples.
p<0.001
Table 1. The 20 genes with highest significance associated with an unfavorable prognosis in GBM.
Favorable prognostic genes in GBMFor favorable genes, higher relative expression levels at diagnosis give significantly higher overall survival for the patients. There are 1088 genes associated with a favorable prognosis in GBM, among these potential prognostic genes there are 12 genes that were validated in a separate study. In Table 2, the top 20 most significant genes related to favorable prognosis are listed. MPST is a gene associated with a favorable prognosis in GBM in two separate independent cohorts. The best separation is achieved by an expression cutoff at 33 TPM which divides the patients into two groups with 17% 3-year survival for patients with high expression versus 2% for patients with low expression, p-value: 2.98e-4. The TCGA data analysis was validated in a separate study with the p-value: 1.71e-5. Immunohistochemical staining using an antibody targeting MPST (HPA001240) shows a differential expression pattern in glioma samples.
p<0.001
Table 2. The 20 genes with highest significance associated with a favorable prognosis in GBM.
CPTAC relative protein expression dataProteins that are significantly down- or upregulated in GBM compared to normal tissue is illustrated in a vulcano plot using tandem mass tag (TMT) mass spectrometry data from the CPTAC dataset based on the analysis of 100 tumor samples and 10 normal samples. In GBM, 2271 and 1491 genes are down- (blue) and upregulated (red) compared to normal tissue, respectively. In Table 3, the top 20 most significant genes are listed.
Table 3. The 20 genes with the highest significance associated with a downregulated or upregulated protein expression in GBM compared to normal tissue.
The GBM transcriptomeThe transcriptome analysis shows that 71% (n=14220) of all human genes (n=20162) are expressed in GBM. All genes were classified according to the GBM-specific expression into one of five different categories, based on the ratio between mRNA levels in glioblastoma multiforme compared to the mRNA levels in the other 16 analyzed cancer tissues.
Figure 2. The distribution of all genes across the five categories based on transcript abundance in GBM as well as in all other cancer tissues. 972 genes show some level of elevated expression in GBM compared to other cancers (Figure 1). The elevated category is further subdivided into three categories as shown in Table 3. Table 4. The number of genes in the subdivided categories of elevated expression in GBM.
Additional informationThe classification of gliomas is based on cell type, grade, and location. Cell type classification is divided into 6 main categories; astrocytoma, oligodendrogliomas, brain stem gliomas, ependymomas, oligo-astrocytomas, and optic pathway gliomas. Grade classification is divided into low-grade (benign tendencies) and high-grade gliomas (malignant). Gliomas can also be classified according to whether they are above or below the tentorium, a membrane in the brain that separates the cerebrum from the cerebellum. The classification is supertentorium (cerebrum) and infratentorium (cerebellum), there is also one more known as pontine tumors and is located in the brainstem. Astrocytomas represent almost half of all brain tumors and are defined based on morphological features such as cellularity, nuclear atypia, mitotic rate, endothelial proliferation, and necrosis. Astrocytomas are assigned to grades I-IV according to the current WHO classification system. These include pilocytic astrocytoma (Grade I), astrocytoma (Grade II), anaplastic astrocytoma (Grade III), and glioblastoma (Grade IV). The various forms of glioma are highly variable and several phenotypically different cell types exist, including gemistocytic glioma cells. Gemistocytic cells resemble a morphological alteration that can also be found in reactive astrocytes and is characterized by eosinophilic staining of a large, swollen cytoplasm. Approximately 15% of gliomas are oligodendrogliomas. Histologically, oligodendrogliomas commonly show uniform cell architecture with increased numbers of delicate blood vessels. The tumor cell nuclei are mainly round and regular and often surrounded by an artifactual perinuclear clearing that results in the so called "fried egg" appearance. High-grade oligodendrogliomas (anaplastic oligodendrogliomas) are recognized by features such as increased cellularity, mitotic activity and nuclear pleomorphism, as well as necrosis and endothelial proliferation. The distinction between different forms of brain tumors is mainly based on morphological features, but immunohistochemistry plays an important role to distinguish between different tumor types, in particular when the tumor is poorly differentiated. In neuropathological diagnostics, antibodies directed towards proteins such as Glial Fibrillary Acidic Protein, Synaptophysin, EGFR, p53, and the proliferation marker Ki-67 are commonly used. Relevant links and publications Uhlen M et al., A pathology atlas of the human cancer transcriptome. Science. (2017) MedScape - Glioblastoma Multiforme |
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