LRP1B deletion is associated with poor outcome for glioblastoma patients.

INTRODUCTION: Deletion of the tumor suppressor gene LRP1B has been reported in glioblastoma, the most aggressive primary brain tumor in adults. Our objective was to analyze frequency and prognostic impact of LRP1B deletion and expression levels. METHODS: We retrospectively included all the primary IDH1/2 wild-type GBM patients with available clinical follow-up, DNA and RNA from our database. Deletions were analyzed by SNP-array. LRP1B mRNA expression was analyzed by reverse transcription quantitative polymerase chain reaction. RESULTS: 178 patients were included with a median age of 62.36 years. LRP1B deletions were observed for 10.1% of patients (complete: 2.8%, partial: 7.3%). LRP1B deletions were associated with poor progression-free survival (PFS) (p=0.004) and overall survival (OS) (p=0.001). By multivariate analysis, LRP1B deletions remained significant for both PFS (p=0.003, hazard ratio (HR): 2.261) and OS (p=0.001, HR: 2.609). LRP1B was down expressed with a mean relative expression of 46% comparatively to normal tissue. No association between LRP1B mRNA and patient outcome was observed. No correlation was found between the deletions and the mRNA down-expression. These results were validated using GBM TCGA data. CONCLUSION: LRP1B presents with frequent molecular alterations which impact patient outcome, highlighting the potential interest of this gene for glioblastoma patients.

TERT promoter mutations in gliomas, genetic associations and clinico-pathological correlations.

BACKGROUND: The role of telomerase reverse transcriptase (TERT) in gliomagenesis has been recently further strengthened by the frequent occurrence of TERT promoter mutations (TERTp-mut) in gliomas and evidence that the TERT SNP genetic rs2736100 influences glioma risk. TERTp-mut creates a binding site for Ets/TCF transcription factors, whereas the common rs2853669 polymorphism disrupts another Ets/TCF site on TERT promoter. METHODS: We sequenced for TERTp-mut in 807 glioma DNAs and in 235 blood DNAs and analysed TERT expression by RT-PCR in 151 samples. TERTp-mut status and TERTp polymorphism rs2853669 were correlated with histology, genomic profile, TERT mRNA expression, clinical outcome and rs2736100 genotype. RESULTS: TERTp-mut identified in 60.8% of gliomas (491 out of 807) was globally associated with poorer outcome (Hazard ratio (HR)=1.50). We defined, based on TERTp-mut and IDH mutation status, four prognostic groups: (1) TERTp-mut and IDH-mut associated with 1p19q codeletion, overall survival (OS)>17 years; (2) TERTp-wt and IDH-mut, associated with TP53 mutation, OS=97.5 months; (3) TERTp-wt and IDH-wt, with no specific association, OS=31.6 months; (4) TERTp-mut and IDH-wt, associated with EGFR amplification, OS=15.4 months. TERTp-mut was associated with higher TERT mRNA expression, whereas the rs2853669 variant was associated with lower TERT mRNA expression. The mutation of CIC (a repressor of ETV1-5 belonging to the Ets/TCF family) was also associated with TERT mRNA upregulation. CONCLUSIONS: In addition to IDH mutation status, defining the TERTp-mut status of glial tumours should afford enhanced prognostic stratification of patients with glioma. We also show that TERTp-mut, rs2853669 variant and CIC mutation influence Tert expression. This effect could be mediated by Ets/TCF transcription factors.

Low penetrance susceptibility to glioma is caused by the TP53 variant rs78378222.

BACKGROUND: Most of the heritable risk of glioma is presently unaccounted for by mutations in known genes. In addition to rare inactivating germline mutations in TP53 causing glioma in the context of the Li-Fraumeni syndrome, polymorphic variation in TP53 may also contribute to the risk of developing glioma. METHODS: To comprehensively evaluate the impact of variation in TP53 on risk, we analysed 23 tagSNPs and imputed 2377 unobserved genotypes in four series totaling 4147 glioma cases and 7435 controls. RESULTS: The strongest validated association signal was shown by the imputed single-nucleotide polymorphism (SNP) rs78378222 (P=6.86 × 10(-24), minor allele frequency ~0.013). Confirmatory genotyping confirmed the high quality of the imputation. The association between rs78378222 and risk was seen for both glioblastoma multiforme (GBM) and non-GBM tumours. We comprehensively examined the relationship between rs78378222 and overall survival in two of the case series totaling 1699 individuals. Despite employing statistical tests sensitive to the detection of differences in early survival, no association was shown. CONCLUSION: Our data provided strong validation of rs78378222 as a risk factor for glioma but do not support the tenet that the polymorphism being a clinically useful prognostic marker. Acquired TP53 inactivation is a common feature of glioma. As rs78378222 changes the polyadenylation signal of TP53 leading to impaired 3'-end processing of TP53 mRNA, the SNP has strong plausibility for being directly functional contributing to the aetiological basis of glioma.

Metabolism of glioma and IDH1/IDH2 mutations.

Many known oncogenic signaling pathways involved in gliomagenesis have strong consequences on tumor cell metabolism, and promote the switch from oxidative phosphorylation to aerobic glycolysis, for ATP generation. However, the interest on metabolism has been recently renewed by the discovery of recurrent mutation of IDH1 genes by systematic sequencing of a glioblastoma series. IDH1 encodes the cytoplasmic NADP dependent isocitrate dehydrogenase1 that catalyzes the oxidative decarboxylation of isocitrate into α-ketoglutarate. IDH1, more rarely IDH2, is mutated in 40% of gliomas (roughly 70% of low-grade gliomas, 50% of grade III, and 5 to 10% of primary glioblastomas). IDH1/IDH2 mutations are associated with genomic profile, being present in nearly all the 1p19q codeleted gliomas, and virtually absent in gliomas with EGFR amplification. It is a strong and independent predictor of survival, whatever grade considered. IDH1/IDH2 mutation results in a new enzymatic activity transforming α-ketoglutarate into 2-hydroxyglutarate (2-HG). The oncometabolite 2-HG accumulates in the cell and acts as a competitive inhibitor of many α-ketoglutarate dependent cellular reactions. The cellular consequences of this mutation offer potential targets for the development of novel therapeutics.

All the 1p19q codeleted gliomas are mutated on IDH1 or IDH2.

BACKGROUND: Recently, the gene encoding the human cytosolic NADPH-dependent isocitrate dehydrogenase (IDH1) was reported frequently mutated in gliomas. Rare mutations were also found in the sequence of the mitochondrial isoform IDH2. METHODS: In a series of 764 gliomas genome-wide characterized, we determined the presence of mutations in the sequences of both IDH1 and IDH2 genes by direct sequencing. RESULTS: We found that all tumors with complete 1p19q codeletion (n = 128) were mutated in the IDH1 (118) or IDH2 (10) gene. This 100% mutation rate contrasted strikingly with other gliomas exhibiting either variable 1p and 19q alterations (n = 159, IDH1/IDH2 mutation rate of 33%) or no 1p19q alteration (n = 477, IDH1/IDH2 mutation rate 32%). Our data also confirm the prognostic impact of IDH1/IDH2 mutation in gliomas whatever grade considered: patients harboring mutations of IDH1/IDH2 have an improved median overall survival. Moreover, in WHO grade II and III gliomas, 3 groups with significantly different outcomes were identified according to their 1p19q and IDH1/IDH2 statuses. Tumors carrying both alterations had longer overall survival than their nonmutated counterpart. CONCLUSIONS: This exclusive association suggests a new mechanism of tumorigenesis. Perhaps the IDH1/IDH2 mutation is a prerequisite for the occurrence of the t(1;19) translocation, or it is required for the 1p19q codeleted cells to acquire a tumor phenotype.