The Somatic Genomic Landscape of Glioblastoma

Abstract

We describe the landscape of somatic genomic alterations based on multi-dimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.

Retracted: MircoRNA‐1275 promotes proliferation, invasion and migration of glioma cells via SERPINE1

“…P53 has been known to mutate in more than 50% of human cancers,13 including glioma. A previous study found that p53 signalling pathway was found to be dysregulated in 85.3% of glioma patients according to the TCGA (The Cancer Genome Atlas) data 14. Herein, we analysed signalling pathways closely related to glioma using Gene Set Enrichment Analysis (GSEA) to confirm the aberrant condition of p53 pathway.…”

The TERT promoter mutation status and MGMT promoter methylation status, combined with dichotomized MRI‐derived and clinical features, predict adult primary glioblastoma survival

“…The validation of their prognostic function by Kaplan‐Meier and Cox PH regression analyses revealed that age and the MGMT promoter methylation status were important prognostic markers that provide independent information. Primary GBM comprises 84.21% (265/304) of all adult GBM patients, and this ratio is lower than that reported in previous studies 1, 6. This discrepancy might be due to the classification of primary and secondary GBM based on the clinical history or IDH1/2 status in previous studies.…”

“…Among the five important variables identified in the random survival forest analysis, the MGMT promoter methylation status and TERT promoter mutation status are key molecular tumor markers of GBM 6. We analyzed the relationship between the MGMT promoter methylation status and the survival benefit associated with the TERT promoter mutation status.…”

“…Correspondingly, wild‐type IDH1/2 genotypes are considered robust biomarkers of primary GBM (<5%) 4, 5. Epigenetic alterations affecting the MGMT promoter methylation status and genetic mutations in the TERT promoter are considered molecular signatures of GBM,6 but few studies have investigated the prognostic significance of these molecular features in adult primary GBM. The diagnosis and monitoring of GBMs in neurosurgical practice are often accomplished through MRI visualization.…”

KLRC3, a Natural Killer receptor gene, is a key factor involved in glioblastoma tumourigenesis and aggressiveness

“…Moreover, in a cohort of 154 patients with glioblastoma, KLRC3 has been founded mutated in 6% of the cases. By comparing the median survival of the patients included in the cohort, we founded a strong increase from 13.3 months for the patients without mutation to 25.4 months of survival for the patients having a mutated KLRC3 (from the TCGA analysis: The Cancer Genome Atlas) 16.…”