SHOX2 is a Potent Independent Biomarker to Predict Survival of WHO Grade II–III Diffuse Gliomas

Yu An Zhang, Yunyun Zhou, Xin Luo, Kai Song, Xiaotu Ma, Adwait Sathe, Luc Girard, Guanghua Xiao, Adi F. Gazdar

Research output: Contribution to journalArticle

6 Citations (Scopus)

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. Findings 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. Interpretation 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.

Original languageEnglish (US)
Pages (from-to)80-89
Number of pages10
JournalEBioMedicine
Volume13
DOIs
StatePublished - Nov 1 2016

Fingerprint

Methylation
Biomarkers
Glioma
Survival
Genes
Histology
Chromosomes
Gene expression
Tumors
Gene Expression
Chromosome Deletion
Atlases
Homeobox Genes
Kaplan-Meier Estimate
Proportional Hazards Models
Patient Selection
Neoplasms
Multivariate Analysis

Keywords

  • Astrocytomas
  • Gliomas
  • IDH mutation
  • Oligodendrogliomas
  • Prognosis
  • SHOX2 biomarker

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Zhang, Y. A., Zhou, Y., Luo, X., Song, K., Ma, X., Sathe, A., ... Gazdar, A. F. (2016). SHOX2 is a Potent Independent Biomarker to Predict Survival of WHO Grade II–III Diffuse Gliomas. EBioMedicine, 13, 80-89. https://doi.org/10.1016/j.ebiom.2016.10.040

SHOX2 is a Potent Independent Biomarker to Predict Survival of WHO Grade II–III Diffuse Gliomas. / Zhang, Yu An; Zhou, Yunyun; Luo, Xin; Song, Kai; Ma, Xiaotu; Sathe, Adwait; Girard, Luc; Xiao, Guanghua; Gazdar, Adi F.

In: EBioMedicine, Vol. 13, 01.11.2016, p. 80-89.

Research output: Contribution to journalArticle

Zhang, Yu An ; Zhou, Yunyun ; Luo, Xin ; Song, Kai ; Ma, Xiaotu ; Sathe, Adwait ; Girard, Luc ; Xiao, Guanghua ; Gazdar, Adi F. / SHOX2 is a Potent Independent Biomarker to Predict Survival of WHO Grade II–III Diffuse Gliomas. In: EBioMedicine. 2016 ; Vol. 13. pp. 80-89.
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AU - Zhou, Yunyun

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AU - Song, Kai

AU - Ma, Xiaotu

AU - Sathe, Adwait

AU - Girard, Luc

AU - Xiao, Guanghua

AU - Gazdar, Adi F.

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N2 - 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. Findings 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. Interpretation 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.

AB - 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. Findings 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. Interpretation 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.

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