title: SHOX2 is a Potent Independent Biomarker to Predict Survival of WHO Grade II-III Diffuse Gliomas.
abstract: BACKGROUND
  Diffuse gliomas, grades II and III, hereafter called lower-grade gliomas (LGG), have variable, difficult to predict clinical courses, resulting in multiple studies to identify prognostic biomarkers. The purpose of this study was to assess expression or methylation of the homeobox family gene SHOX2 as independent markers for LGG survival.
  
  
  METHODS
  We downloaded publically available glioma datasets for gene expression and methylation. The Cancer Genome Atlas (TCGA) (LGG, n=516) was used as a training set, and three other expression datasets (n=308) and three other methylation datasets (n=320), were used for validation. We performed Kaplan-Meier survival curves and univariate and multivariate Cox regression model analyses.
  
  
  RESULTS
  SHOX2 expression and gene body methylation varied among LGG patients and highly significantly predicted poor overall survival. While they were tightly correlated, SHOX2 expression appeared more potent as a prognostic marker and was used for most further studies. The SHOX2 prognostic roles were maintained after analyses by histology subtypes or tumor grade. We found that the combination of SHOX2 expression and IDH genotype status identified a subset of LGG patients with IDH wild-type (IDHwt) and low SHOX2 expression with considerably favorable survival. We further investigated the combination of SHOX2 with other known clinically relevant markers of LGG (TERT expression, 1p/19q chromosome co-deletion, MGMT methylation, ATRX mutation and NES expression). When combined with SHOX2 expression, we identified subsets of LGG patients with significantly favorable survival outcomes, especially in the subgroup with worse prognosis for each individual marker. Finally, multivariate analysis demonstrated that SHOX2 was a potent independent survival marker.
  
  
  CONCLUSIONS
  We have identified that SHOX2 expression or methylation are potent independent prognostic indicators for predicting LGG patient survival, and have potential to identify an important subset of LGG patients with IDHwt status with significantly better overall survival. The combination of IDH or other relevant markers with SHOX2 identified LGG subsets with significantly different survival outcomes, and further understanding of these subsets may benefit therapeutic target identification and therapy selections for glioma patients.
authors.affiliation: The Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Yu-An
authors.initials: YA
authors.lastname: Zhang
authors.affiliation: Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Center of Biostatistics and Bioinformatics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Luo
authors.affiliation: School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Song
authors.affiliation: Department of Computational Biology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, USA.
authors.forename: Xiaotu
authors.initials: X
authors.lastname: Ma
authors.affiliation: The Center for Systems Biology, Department of Molecular and Cell Biology, The University of Texas at Dallas, Richardson, TX, 75080, USA.
authors.forename: Adwait
authors.initials: A
authors.lastname: Sathe
authors.affiliation: The Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Luc
authors.initials: L
authors.lastname: Girard
authors.affiliation: Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; The Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Guanghua
authors.initials: G
authors.lastname: Xiao
authors.affiliation: The Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; The Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: adi.gazdar@utsouthwestern.edu.
authors.forename: Adi F
authors.initials: AF
authors.lastname: Gazdar
mesh_terms: D014408:Biomarkers, Tumor; D001932:Brain Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D019295:Computational Biology / Q000379:methods; D019175:DNA Methylation; D030561:Databases, Nucleic Acid; D020869:Gene Expression Profiling; D005910:Glioma / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D009154:Mutation; D060787:Neoplasm Grading; D011379:Prognosis; D016016:Proportional Hazards Models; D059467:Transcriptome
chemical_list: D014408:Biomarkers, Tumor; D018398:Homeodomain Proteins; C484664:SHOX2 protein, human; D007521:Isocitrate Dehydrogenase
keywords: Astrocytomas; Gliomas; IDH mutation; Oligodendrogliomas; Prognosis; SHOX2 biomarker