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.

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.

Highlight

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  SHOX2 is a potent independent prognostic indicator for grade II and III diffuse gliomas. SHOX2 in combination with IDH has the potential to identify important diffuese gliomas subsets with significantly better survivals. SHOX2 in combination with other markers is potentially useful for identifying distinct prognostic subsets of diffuse gliomas.

Diffuse glioma brain tumors (gliomas encompassing astrocytomas and oligodedrogliomas, grades II and III), have highly variable, difficult to predict clinical courses and a number of specific alterations have been identified that have prognostic or therapeutic implications, whether as single markers or in various combinations. The use of mutation status of the isocitrate dehydrogenase ( IDH) enzyme genes has been demonstrated to be a potent prognostic marker greatly improving survival prognosis. SHOX2 methylation was suggested to be associated with lung and breast cancers. In this study we assessed SHOX2 gene methylation and expression as independent markers for diffuse gliomas survival prognosis, by multiple statistical survival analyses of multiple genome-wide datasets. We have identified that SHOX2 is a potent independent prognostic marker, both by itself and in combination with other markers ( IDH mutation status, 1p/19q codeltion, ATRX mutation, nestin or TERT expression and MGMT methylation), and potentially useful for refining the molecular classification of diffuse gliomas, and for distinguishing clinically distinct prognostic subgroups of gliomas patients for better therapy selection.