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AKT pathway genes define 5 prognostic subgroups in glioblastoma

Joy A1, Ramesh A2, Smirnov I3, Reiser M4, Misra A1, Shapiro WR1, Mills GB5, Kim S6, Feuerstein BG7.

PLoS One. 2014 ;9(7):e100827.

1Department of Neurology, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, United States of America.and

2University of Washington, Tacoma, Washington, United States of America.and

3Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States of America.and

4Department of Mathematics and Statistical Science, Arizona State University, Tempe, Arizona, United States of America.and

5Department of Systems Biology, MD Anderson Cancer Center, Houston, Texas, United States of America.and

6Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.and

7Department of Neurology, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, United States of America; University of Arizona College of Medicine, Phoenix, Arizona, United States of America.

 

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.

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