A Prognostic Signature for Lower Grade Gliomas Based on Expression of Long Non-Coding RNAs

Abstract

Diffuse low-grade and intermediate-grade gliomas (together known as lower grade gliomas, WHO grade II and III) develop in the supporting glial cells of brain and are the most common types of primary brain tumor. Despite a better prognosis for lower grade gliomas, 70% of patients undergo high-grade transformation within 10 years, stressing the importance of better prognosis. Long non-coding RNAs (lncRNAs) are gaining attention as potential biomarkers for cancer diagnosis and prognosis. We have developed a computational model, UVA8, for prognosis of lower grade gliomas by combining lncRNA expression, Cox regression, and L1-LASSO penalization. The model was trained on a subset of patients in TCGA. Patients in TCGA, as well as a completely independent validation set (CGGA) could be dichotomized based on their risk score, a linear combination of the level of each prognostic lncRNA weighted by its multivariable Cox regression coefficient. UVA8 is an independent predictor of survival and outperforms standard epidemiological approaches and previous published lncRNA-based predictors as a survival model. Guilt-by-association studies of the lncRNAs in UVA8, all of which predict good outcome, suggest they have a role in suppressing interferon-stimulated response and epithelial to mesenchymal transition. The expression levels of eight lncRNAs can be combined to produce a prognostic tool applicable to diverse populations of glioma patients. The 8 lncRNA (UVA8) based score can identify grade II and grade III glioma patients with poor outcome, and thus identify patients who should receive more aggressive therapy at the outset.

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Abbreviations

lncRNA:

Long non-coding RNAs

WHO:

World Health Organization

LGG:

Lower grade gliomas

GBM:

Glioblastoma multiforme

CNS:

Central nervous system

TCGA:

The Cancer Genome Atlas

CGGA:

Chinese Glioma Genome Atlas

HR:

Hazard ratio

PFS:

Progression-free survival

IFNG:

Interferon gamma

Cindex:

Concordance index

AUC:

Area under curve

ROC:

Receiver operating characteristics

UVA8:

University of Virginia 8

L1-LASSO:

L1 least absolute shrinkage and selection operator

MGMT:

O6-methylguanine DNA methyltransferase

FPKM:

Fragment per kilobase per million

GTF:

Gene transfer format

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Acknowledgments

We thank Dr. Stefan Bekiranov, Dr. William Pearson, and Dutta lab members for helpful discussions. M.K. is supported by a DOD award PC151085.

Funding

The work was supported by a V foundation award D2018-002 and R01 AR067712 from NIAMS.

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Correspondence to Anindya Dutta.

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Kiran, M., Chatrath, A., Tang, X. et al. A Prognostic Signature for Lower Grade Gliomas Based on Expression of Long Non-Coding RNAs. Mol Neurobiol 56, 4786–4798 (2019). https://doi.org/10.1007/s12035-018-1416-y

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Keywords

  • Long non-coding RNAs
  • Gliomas
  • Gene expression profiling
  • Prognosis