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AKT pathway genes define 5 prognostic subgroups in glioblastoma.

ABSTRACT: Activity of GFR/PI3K/AKT pathway inhibitors in glioblastoma clinical trials has not been robust. We hypothesized variations in the pathway between tumors contribute to poor response. We clustered GBM based on AKT pathway genes and discovered new subtypes then characterized their clinical and molecular features. There are at least 5 GBM AKT subtypes having distinct DNA copy number alterations, enrichment in oncogenes and tumor suppressor genes and patterns of expression for PI3K/AKT/mTOR signaling components. Gene Ontology terms indicate a different cell of origin or dominant phenotype for each subgroup. Evidence suggests one subtype is very sensitive to BCNU or CCNU (median survival 5.8 vs. 1.5 years; BCNU/CCNU vs other treatments; respectively). AKT subtyping advances previous approaches by revealing additional subgroups with unique clinical and molecular features. Evidence indicates it is a predictive marker for response to BCNU or CCNU and PI3K/AKT/mTOR pathway inhibitors. We anticipate Akt subtyping may help stratify patients for clinical trials and augment discovery of class-specific therapeutic targets.

SUBMITTER: Joy A

PROVIDER: S-EPMC4077731 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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AKT pathway genes define 5 prognostic subgroups in glioblastoma.

Joy Anna A Ramesh Archana A Smirnov Ivan I Reiser Mark M Misra Anjan A Shapiro William R WR Mills Gordon B GB Kim Seungchan S Feuerstein Burt G BG

PloS one 20140701 7

Activity of GFR/PI3K/AKT pathway inhibitors in glioblastoma clinical trials has not been robust. We hypothesized variations in the pathway between tumors contribute to poor response. We clustered GBM based on AKT pathway genes and discovered new subtypes then characterized their clinical and molecular features. There are at least 5 GBM AKT subtypes having distinct DNA copy number alterations, enrichment in oncogenes and tumor suppressor genes and patterns of expression for PI3K/AKT/mTOR signalin ...[more]

PMID: 24984002

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Project description:Increasing studies have proved that malignant tumors are associated with energy metabolism. This study was aimed to explore biological variables that impact the prognosis of patients in the glycolysis-related subgroups of lung adenocarcinoma (LUAD). The mRNA expression profiling and mutation data in large LUAD samples were collected from the Cancer Genome Atlas (TCGA) database. Then, we identified the expression level and prognostic value of glycolysis-related genes, as well as the fractions of 22 immune cells in the tumor microenvironment. The differences between glycolysis activity, mutation, and immune infiltrates were discussed in these groups, respectively. Two hundred fifty-five glycolysis-related genes were identified from gene set enrichment analysis (GSEA), of which 43 genes had prognostic values (p < 0.05). Next, we constructed a glycolysis-related competing endogenous RNA (ceRNA) network which related to the survival of LUAD. Then, two subgroups of LUAD (clusters 1 and 2) were identified by applying unsupervised consensus clustering to 43 glycolysis-related genes. The survival analysis showed that the cluster 1 patients had a worse prognosis (p < 0.001), and upregulated differentially expressed genes (DEGs) are interestingly enriched in malignancy-related biological processes. The differences between the two subgroups are SPTA1, KEAP1, USH2A, and KRAS among top 10 mutated signatures, which may be the underlying mechanism of grouping. Combined high tumor mutational burden (TMB) with tumor subgroups preferably predicts the prognosis of LUAD patients. The CIBERSORT algorithm results revealed that low TMB samples were concerned with increased infiltration level of memory resting CD4+ T cell (p = 0.03), resting mast cells (p = 0.044), and neutrophils (p = 0.002) in cluster 1 and high TMB samples were concerned with increased infiltration level of memory B cells, plasma cells, CD4 memory-activated T cells, macrophages M1, and activated mast cells in cluster 2, while reduced infiltration of monocytes, resting dendritic cells, and resting mast cells was captured in cluster 2. In conclusion, significant different gene expression characteristics were pooled according to the two subgroups of LUAD. The combination of subgroups, TMB and tumor-infiltrating immune cell signature, might be a novel prognostic biomarker in LUAD.

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AKT pathway genes define 5 prognostic subgroups in glioblastoma.

Publications

AKT pathway genes define 5 prognostic subgroups in glioblastoma.

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