RESUMO
Genome-wide association studies (GWAS) have transformed our understanding of glioma susceptibility, but individual studies have had limited power to identify risk loci. We performed a meta-analysis of existing GWAS and two new GWAS, which totaled 12,496 cases and 18,190 controls. We identified five new loci for glioblastoma (GBM) at 1p31.3 (rs12752552; P = 2.04 × 10-9, odds ratio (OR) = 1.22), 11q14.1 (rs11233250; P = 9.95 × 10-10, OR = 1.24), 16p13.3 (rs2562152; P = 1.93 × 10-8, OR = 1.21), 16q12.1 (rs10852606; P = 1.29 × 10-11, OR = 1.18) and 22q13.1 (rs2235573; P = 1.76 × 10-10, OR = 1.15), as well as eight loci for non-GBM tumors at 1q32.1 (rs4252707; P = 3.34 × 10-9, OR = 1.19), 1q44 (rs12076373; P = 2.63 × 10-10, OR = 1.23), 2q33.3 (rs7572263; P = 2.18 × 10-10, OR = 1.20), 3p14.1 (rs11706832; P = 7.66 × 10-9, OR = 1.15), 10q24.33 (rs11598018; P = 3.39 × 10-8, OR = 1.14), 11q21 (rs7107785; P = 3.87 × 10-10, OR = 1.16), 14q12 (rs10131032; P = 5.07 × 10-11, OR = 1.33) and 16p13.3 (rs3751667; P = 2.61 × 10-9, OR = 1.18). These data substantiate that genetic susceptibility to GBM and non-GBM tumors are highly distinct, which likely reflects different etiology.
Assuntos
Neoplasias Encefálicas/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Glioblastoma/genética , Glioma/genética , Alelos , Neoplasias Encefálicas/classificação , Regulação Neoplásica da Expressão Gênica , Genótipo , Glioblastoma/classificação , Glioma/classificação , Humanos , Metanálise como Assunto , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genéticaRESUMO
BACKGROUND: The 1p19q non-codeleted gliomas with IDH mutation, defined as "molecular astrocytomas," display frequent TP53 mutations and have an intermediate prognosis. We investigated the prognostic impact of copy number-neutral loss of heterozygosity (CNLOH) in 17p in this population. METHODS: We analyzed 793 gliomas (206 grade II, 377 grade III, and 210 grade IV) by single nucleotide polymorphism array and for TP53 mutations. RESULTS: Homodisomy revealed by CNLOH was observed in 156 cases (19.7%). It was more frequent in astrocytomas and oligoastrocytomas (98/256, 38%) than oligodendrogliomas (28/327, 8.6%; p < .0001) or glioblastoma multiforme (30/210, 14.3%; p < .0001), tightly associated with TP53 mutation (69/71 vs. 20/79; p = 2 × 10(-16)), and mutually exclusive with 1p19q codeletion (1/156 vs. 249/556; p < .0001). In the group of IDH-mutated 1p19q non-codeleted gliomas, CNLOH 17p was associated with longer survival (86.3 vs. 46.2 months; p = .004), particularly in grade III gliomas (overall survival >100 vs. 37.9 months; p = .007). These data were confirmed in an independent dataset from the Cancer Genome Atlas. CONCLUSION: CNLOH 17p is a prognostic marker and further refines the molecular classification of gliomas. IMPLICATIONS FOR PRACTICE: Homodisomy of chromosome 17p (CNLOH 17p) is a frequent feature in IDH-mutated 1p19q non-codeleted gliomas (group 2). It is constantly associated with TP53 mutation. It was found, within this specific molecular group of gliomas (corresponding to molecular astrocytomas), that CNLOH 17p is associated with a much better outcome and may therefore represent an additional prognostic marker to refine the prognostic classification of gliomas.
Assuntos
Glioma/genética , Isocitrato Desidrogenase/genética , Perda de Heterozigosidade/genética , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Cromossomos Humanos Par 17/genética , Intervalo Livre de Doença , Feminino , Glioma/epidemiologia , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , PrognósticoRESUMO
Despite encouraging response rate of bevacizumab (BVZ) in recurrent glioblastoma, many patients do not respond to this schedule and most of the responders develop an early relapse. Plasma concentrations of VEGF, PlGF, Ang2, and sTie2 were assessed by ELISA before and during BVZ treatment in seventy patients. Baseline levels of VEGF-A, and PlGF were higher in patients than in healthy volunteers, whereas no difference was found for Ang2, and sTie2. No biomarker at baseline was associated with response, PFS or OS. At recurrence, the authors observed an increase of Ang2 suggesting that Ang2/sTie2 could be involved in the resistance to BVZ.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Angiopoietina-2/sangue , Antineoplásicos/uso terapêutico , Bevacizumab/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/sangue , Glioblastoma/tratamento farmacológico , Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Bevacizumab/farmacologia , Biomarcadores , Estudos de Casos e Controles , Progressão da Doença , Feminino , Glioblastoma/mortalidade , Glioblastoma/patologia , Glioblastoma/secundário , Humanos , Masculino , Proteínas de Membrana/sangue , Recidiva Local de Neoplasia , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
To identify protein-altering variants (PAVs) for glioma, we analysed Illumina HumanExome BeadChip exome-array data on 1882 glioma cases and 8079 controls from three independent European populations. In addition to single-variant tests we incorporated information on the predicted functional consequences of PAVs and analysed sets of genes with a higher likelihood of having a role in glioma on the basis of the profile of somatic mutations documented by large-scale sequencing initiatives. Globally there was a strong relationship between effect size and PAVs predicted to be damaging (P=2.29 × 10(-49)); however, these variants which are most likely to impact on risk, are rare (MAF<5%). Although no single variant showed an association which was statistically significant at the genome-wide threshold a number represented promising associations - BRCA2:c.9976A>T, p.(Lys3326Ter), which has been shown to influence breast and lung cancer risk (odds ratio (OR)=2.3, P=4.00 × 10(-4) for glioblastoma (GBM)) and IDH2:c.782G>A, p.(Arg261His) (OR=3.21, P=7.67 × 10(-3), for non-GBM). Additionally, gene burden tests revealed a statistically significant association for HARS2 and risk of GBM (P=2.20 × 10(-6)). Genome scans of low-frequency PAVs represent a complementary strategy to identify disease-causing variants compared with scans based on tagSNPs. Strategies to lessen the multiple testing burden by restricting analysis to PAVs with higher priors affords an opportunity to maximise study power.
Assuntos
Neoplasias Encefálicas/genética , Exoma , Loci Gênicos , Técnicas de Genotipagem/métodos , Glioma/genética , Polimorfismo de Nucleotídeo Único , Algoritmos , Aminoacil-tRNA Sintetases/genética , Proteína BRCA2/genética , Estudos de Casos e Controles , Feminino , Humanos , Isocitrato Desidrogenase/genética , Masculino , Pessoa de Meia-IdadeRESUMO
TERT promoter (TERTp) mutation is the most common mutation in glioblastomas. It creates a putative binding site for Ets/TCF transcription factors, enhancing telomerase expression and activity, whereas the rs2853669 variant disrupts another Ets/TCF binding. We explore here the interaction between these two alterations, tumor genomic profile and the impact on prognosis. The TERTp and rs2853669 statuses were determined and confronted with the outcome and molecular profile, i.e., loss of chromosome 10q, CDKN2A deletion, IDH mutation, EGFR amplification, MGMT promoter methylation. 651 glioblastomas were selected (sex ratio = 1.35, median age 60.4 years, median survival 13.5 months). The TERTp mutation found in 481 patients (74 %) was independent from rs2853669 genotypes. TERTp mutation, but not rs2853669 status, was associated with older age (61.4 vs. 52.8 years). rs2853669 status had no impact on overall survival (OS) either in mutated TERTp or wild-type TERTp. Neither rs2736100 (TERT, 5q15.33) nor rs192011116 (TERC, 3q26.2) status had any impact on survival or showed any association with a TERTp mutation. The TERTp mutation was associated with EGFR amplification chromosome 10q loss, CDKN2A deletion and IDH wt. EGFR amplification was associated with a better outcome in TERTp mutated GBM, and a worse outcome in TERTp WT. This study-the largest analyzing the TERTp mutation and the rs2853669 polymorphism-fails to find any prognostic impact of rs2853669. It confirms the dual prognostic impact of EGFR amplification depending on TERTp status.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Glioblastoma/genética , Mutação/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Telomerase/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/patologia , Feminino , Seguimentos , Genótipo , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Reação em Cadeia da Polimerase , Prognóstico , Taxa de Sobrevida , Adulto JovemRESUMO
PURPOSE: p53 pathway alterations are key molecular events in glioblastoma (GBM). MDM2 inhibitors increase expression and stability of p53 and are presumed to be most efficacious in patients with TP53 wild-type and MDM2-amplified cancers. However, this biomarker hypothesis has not been tested in patients or patient-derived models for GBM. EXPERIMENTAL DESIGN: We performed a preclinical evaluation of RG7112 MDM2 inhibitor, across a panel of 36 patient-derived GBM cell lines (PDCL), each genetically characterized according to their P53 pathway status. We then performed a pharmacokinetic (PK) profiling of RG7112 distribution in mice and evaluated the therapeutic activity of RG7112 in orthotopic and subcutaneous GBM models. RESULTS: MDM2-amplified PDCLs were 44 times more sensitive than TP53-mutated lines that showed complete resistance at therapeutically attainable concentrations (avg. IC50 of 0.52 µmol/L vs. 21.9 µmol/L). MDM4-amplified PDCLs were highly sensitive but showed intermediate response (avg. IC50 of 1.2 µmol/L), whereas response was heterogeneous in TP53 wild-type PDCLs with normal MDM2/4 levels (avg. IC50 of 7.7 µmol/L). In MDM2-amplified lines, RG7112 restored p53 activity inducing robust p21 expression and apoptosis. PK profiling of RG7112-treated PDCL intracranial xenografts demonstrated that the compound significantly crosses the blood-brain and the blood-tumor barriers. Most importantly, treatment of MDM2-amplified/TP53 wild-type PDCL-derived model (subcutaneous and orthotopic) reduced tumor growth, was cytotoxic, and significantly increased survival. CONCLUSIONS: These data strongly support development of MDM2 inhibitors for clinical testing in MDM2-amplified GBM patients. Moreover, significant efficacy in a subset of non-MDM2-amplified models suggests that additional markers of response to MDM2 inhibitors must be identified.
Assuntos
Glioblastoma/tratamento farmacológico , Imidazolinas/administração & dosagem , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteína Supressora de Tumor p53/genética , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/patologia , Humanos , Camundongos , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Genome-wide association studies (GWAS) have successfully identified a number of common single-nucleotide polymorphisms (SNPs) influencing glioma risk. While these SNPs only explain a small proportion of the genetic risk it is unclear how much is left to be detected by other, yet to be identified, common SNPs. Therefore, we applied Genome-Wide Complex Trait Analysis (GCTA) to three GWAS datasets totalling 3,373 cases and 4,571 controls and performed a meta-analysis to estimate the heritability of glioma. Our results identify heritability estimates of 25% (95% CI: 20-31%, P = 1.15 × 10(-17)) for all forms of glioma - 26% (95% CI: 17-35%, P = 1.05 × 10(-8)) for glioblastoma multiforme (GBM) and 25% (95% CI: 17-32%, P = 1.26 × 10(-10)) for non-GBM tumors. This is a substantial increase from the genetic variance identified by the currently identified GWAS risk loci (~6% of common heritability), indicating that most of the heritable risk attributable to common genetic variants remains to be identified.
Assuntos
Neoplasias Encefálicas/genética , Estudo de Associação Genômica Ampla , Glioma/genética , Polimorfismo de Nucleotídeo Único , Característica Quantitativa Herdável , Adulto , Neoplasias Encefálicas/patologia , Glioma/patologia , Humanos , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Previous genome-wide association studies (GWASs) have shown that common genetic variation contributes to the heritable risk of glioma. To identify new glioma susceptibility loci, we conducted a meta-analysis of four GWAS (totalling 4,147 cases and 7,435 controls), with imputation using 1000 Genomes and UK10K Project data as reference. After genotyping an additional 1,490 cases and 1,723 controls we identify new risk loci for glioblastoma (GBM) at 12q23.33 (rs3851634, near POLR3B, P=3.02 × 10(-9)) and non-GBM at 10q25.2 (rs11196067, near VTI1A, P=4.32 × 10(-8)), 11q23.2 (rs648044, near ZBTB16, P=6.26 × 10(-11)), 12q21.2 (rs12230172, P=7.53 × 10(-11)) and 15q24.2 (rs1801591, near ETFA, P=5.71 × 10(-9)). Our findings provide further insights into the genetic basis of the different glioma subtypes.
Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Glioma/genética , Feminino , Genótipo , Glioma/classificação , Humanos , Masculino , Pessoa de Meia-IdadeAssuntos
Neoplasias do Sistema Nervoso Central/patologia , Corpo Caloso/patologia , Linfoma/patologia , Mutação , Regiões Promotoras Genéticas , Telomerase/genética , Neoplasias do Sistema Nervoso Central/genética , Estudos de Coortes , Análise Mutacional de DNA , Genótipo , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Linfoma/genética , Imageamento por Ressonância MagnéticaRESUMO
OBJECTIVE: CIC gene is frequently mutated in oligodendroglial tumors with 1p19q codeletion. However, clinical and biological impact remain poorly understood. METHODS: We sequenced the CIC gene on 127 oligodendroglial tumors (109 with the 1p19q codeletion) and analyzed patients' outcome. We compared magnetic resonance imaging, transcriptomic profile, and CIC protein expression of CIC wild-type (WT) and mutant gliomas. We compared the level of expression of CIC target genes on Hs683-IDH1(R132H) cells transfected with lentivirus encoding mutant and WT CIC. RESULTS: We found 63 mutations affecting 60 of 127 patients, virtually all 1p19q codeleted and IDH mutated (59 of 60). In the 1p19q codeleted gliomas, CIC mutations were associated with a poorer outcome by uni- (p = 0.001) and multivariate analysis (p < 0.016). CIC mutation prognostic impact was validated on the TCGA cohort. CIC mutant grade II codeleted gliomas spontaneously grew faster than WTs. Transcriptomic analysis revealed an enrichment of proliferative pathways and oligodendrocyte precursor cell gene expression profile in CIC mutant gliomas, with upregulation of normally CIC repressed genes ETV1, ETV4, ETV5, and CCND1. Various missense mutations resulted in CIC protein expression loss. Moreover, a truncating CIC mutation resulted in a defect of nuclear targeting of CIC protein to the nucleus in a human glioma cell line expressing IDH1(R132H) and overexpression of CCND1 and other new target genes of CIC, such as DUSP4 and SPRED1. INTERPRETATION: CIC mutations result in protein inactivation with upregulation of CIC target genes, activation of proliferative pathways, inhibition of differentiation, and poorer outcome in patients with a 1p19q codeleted glioma.
Assuntos
Neoplasias Encefálicas/genética , Cromossomos Humanos Par 19/genética , Cromossomos Humanos Par 1/genética , Glioma/genética , Mutação/genética , Proteínas Repressoras/genética , Adolescente , Adulto , Idoso , Neoplasias Encefálicas/patologia , Feminino , Deleção de Genes , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estrutura Secundária de Proteína , Proteínas Repressoras/química , Adulto JovemRESUMO
Glioblastoma (GBM) is the most common primary malignant brain tumour in adults. Prognosis of GBM patients is poor with median overall survival around 15 months. Temozolomide is the chemotherapeutic agent used in the standard of care of newly diagnosed GBM patients relying on radiotherapy with concurrent chemotherapy followed by chemotherapy alone. Irinotecan has shown some efficacy in recurrent malignant gliomas. Bevacizumab has been combined with irinotecan in the treatment of recurrent GBM and with temozolomide in newly diagnosed GBM. As the efficacy of GBM treatments relies on their brain distribution through the blood brain barrier, the aim of the present preclinical work was to study, in in vivo models, the impact of bevacizumab on brain and tumor distribution of temozolomide and irinotecan. Our results show that bevacizumab pre-treatment was associated with a reduced temozolomide brain distribution in tumor-free mice. In tumor bearing mice, bevacizumab increased temozolomide tumor distribution, although not statistically significant. In both tumor-free and tumor-bearing mice, bevacizumab does not modify brain distribution of irinotecan and its metabolite SN-38. Bevacizumab impacts brain distribution of some anti-tumor drugs and potentially their efficacy in GBM. Further studies are warranted to investigate other therapeutic combination.
Assuntos
Bevacizumab/farmacologia , Neoplasias Encefálicas/metabolismo , Encéfalo/metabolismo , Camptotecina/análogos & derivados , Dacarbazina/análogos & derivados , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos Alquilantes/farmacocinética , Antineoplásicos Fitogênicos/farmacocinética , Encéfalo/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Camptotecina/farmacocinética , Linhagem Celular Tumoral , Dacarbazina/farmacocinética , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Humanos , Irinotecano , Camundongos , Camundongos Nus , Transplante de Neoplasias , Temozolomida , Distribuição TecidualRESUMO
PURPOSE: Oncogenic fusions consisting of fibroblast growth factor receptor (FGFR) and TACC are present in a subgroup of glioblastoma (GBM) and other human cancers and have been proposed as new therapeutic targets. We analyzed frequency and molecular features of FGFR-TACC fusions and explored the therapeutic efficacy of inhibiting FGFR kinase in GBM and grade II and III glioma. EXPERIMENTAL DESIGN: Overall, 795 gliomas (584 GBM, 85 grades II and III with wild-type and 126 with IDH1/2 mutation) were screened for FGFR-TACC breakpoints and associated molecular profile. We also analyzed expression of the FGFR3 and TACC3 components of the fusions. The effects of the specific FGFR inhibitor JNJ-42756493 for FGFR3-TACC3-positive glioma were determined in preclinical experiments. Two patients with advanced FGFR3-TACC3-positive GBM received JNJ-42756493 and were assessed for therapeutic response. RESULTS: Three of 85 IDH1/2 wild-type (3.5%) but none of 126 IDH1/2-mutant grade II and III gliomas harbored FGFR3-TACC3 fusions. FGFR-TACC rearrangements were present in 17 of 584 GBM (2.9%). FGFR3-TACC3 fusions were associated with strong and homogeneous FGFR3 immunostaining. They are mutually exclusive with IDH1/2 mutations and EGFR amplification, whereas they co-occur with CDK4 amplification. JNJ-42756493 inhibited growth of glioma cells harboring FGFR3-TACC3 in vitro and in vivo. The two patients with FGFR3-TACC3 rearrangements who received JNJ-42756493 manifested clinical improvement with stable disease and minor response, respectively. CONCLUSIONS: RT-PCR sequencing is a sensitive and specific method to identify FGFR-TACC-positive patients. FGFR3-TACC3 fusions are associated with uniform intratumor expression of the fusion protein. The clinical response observed in the FGFR3-TACC3-positive patients treated with an FGFR inhibitor supports clinical studies of FGFR inhibition in FGFR-TACC-positive patients.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/genética , Glioma/genética , Proteínas de Fusão Oncogênica/genética , Pirazóis/uso terapêutico , Quinoxalinas/uso terapêutico , Animais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/mortalidade , Análise Mutacional de DNA/métodos , Feminino , Imunofluorescência , Glioma/tratamento farmacológico , Glioma/mortalidade , Humanos , Imuno-Histoquímica , Isocitrato Desidrogenase/genética , Estimativa de Kaplan-Meier , Masculino , Camundongos , Camundongos Nus , Proteínas Associadas aos Microtúbulos/genética , Terapia de Alvo Molecular , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Although anti-VEGF therapy is widely used in high-grade gliomas, no predictor of response or toxicity has been reported yet. We investigated here the association of the functional single nucleotide polymorphism (SNP) rs2010963, located in the 5' untranslated terminal region of the VEGFA gene, with survival, response to bevacizumab (BVZ) and vascular toxicity. The rs2010963 was genotyped by Taqman assay in blood DNA from 954 glioma patients with available survival data, including 225 glioblastoma (GBM) patients treated with BVZ. VEGFA plasma levels were assessed by ELISA in 87 patients before treatment. Thrombo-hemorragic adverse events were recorded during BVZ treatment or not, and in an independent population of 92 GBM patients treated with temozolomide. The CC genotype was associated with the occurrence of thrombo-hemorragic events (CC 25 versus CG 13.5 and GG 5.2 %; P = 0.0044) during BVZ. A similar but weaker and non significant trend was observed in patients not receiving BVZ. A CC genotype was associated with higher levels of plasma VEGFA at baseline (107.6 versus 57.50 pg/mL in heterozygotes (CG) and 52.75 pg/mL in GG patients, P = 0.035 and P = 0.028 respectively). The CC genotype tended to be associated to longer PFS when treated with BVZ (P = 0.05), but not when treated with the temozolomide treatment. Our data suggest that the rs2010963 genotype is associated with longer PFS, higher risk of vascular events in recurrent GBM especially treated with BVZ, and higher plasma VEGFA concentration. It may help to identify patients at risk of vascular adverse events during BVZ treatment.
Assuntos
Inibidores da Angiogênese/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Polimorfismo de Nucleotídeo Único , Fator A de Crescimento do Endotélio Vascular/genética , Bevacizumab , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/mortalidade , Intervalo Livre de Doença , Ensaio de Imunoadsorção Enzimática , Genótipo , Glioblastoma/sangue , Glioblastoma/mortalidade , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Hemorragia/genética , Humanos , Estimativa de Kaplan-Meier , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Trombose/induzido quimicamente , Trombose/epidemiologia , Trombose/genética , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
OBJECTIVE: To identify the prognostic significance of TERT promoter mutations (TERTp-mut) and their associations with common molecular alterations in glioblastomas (GBMs). METHODS: We sequenced the TERTp-mut in DNA from 395 GBMs and analyzed the results with their respective histology, genetic profile (IDH1 mutation, EGFR amplification, CDKN2A homozygous deletion, loss of chromosome 10, TP53 mutation), and overall survival (OS). RESULTS: TERTp-mut were found in 299 of 395 GBMs (75.7%) and were associated with an older age (median 59.6 years for TERTp-mut vs 53.6 years for TERT promoter wild type [TERTp-wt], p < 0.0001). TERTp-mut was an independent factor of poor prognosis (OS = 13.8 vs 18.4 months), in both IDH-mutated (OS = 13.8 vs 37.6 months, p = 0.022) and IDH-wt GBMs (OS = 13.7 vs 17.5 months, p = 0.006). TERTp-mut was associated with IDH-wt, EGFR amplification, CDKN2A deletion, and chromosome 10q loss, but not with MGMT promoter methylation. In the TERTp-wt group, OS was twice longer in EGFR-wt than in EGFR amplification GBMs (OS = 26.6 vs 13.3 months; p = 0.005). In the EGFR-wt group, patients with TERTp-wt had a significantly better outcome (OS = 26.3 vs 12.5 months, p < 0.0001), whereas in the EGFR amplification group, patients with TERTp-mut survived longer (OS = 15.8 vs 13.3 months, p = 0.05). Taken together, the absence of both EGFR amplification and TERTp-mut is associated with longer survival in patients with GBM (26.5 months for patients with IDH-wt, 36.7 months for patients with IDH mutation). CONCLUSIONS: The analysis of TERTp-mut, in combination with EGFR amplification and IDH mutation status, refines the prognostic classification of GBMs.
Assuntos
Neoplasias Encefálicas/genética , Receptores ErbB/genética , Glioblastoma/genética , Isocitrato Desidrogenase/genética , Mutação/genética , Telomerase/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Metilases de Modificação do DNA/genética , Feminino , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto JovemRESUMO
OBJECTIVE: IDH1 codon 132 mutation (mostly Arg132His) is frequently found in gliomas and is associated with longer survival. However, it is still unclear whether IDH1 mutation renders the cell more vulnerable to current treatment, radio- and chemotherapy. MATERIALS AND METHODS: We transduced U87 with wild type IDH1 or IDH1 (R132H) expressing lentivirus and analyzed the radiosensitivity (dose ranging 0 to 10 Gy) under normoxia (20% O2) and moderate hypoxia (1% O2). RESULTS: We observed that IDH1 (R132H) U87 cells grow faster in hypoxia and were more sensitive to radiotherapy (in terms of cell mortality and colony formation assay) compared to nontransduced U87 and IDH1 (wt) cells. This effect was not observed in normoxia. CONCLUSION: These data suggest that IDH1 (R132H) mutation increases radiosensitivity in mild hypoxic conditions.
Assuntos
Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/radioterapia , Glioma/patologia , Glioma/radioterapia , Isocitrato Desidrogenase/genética , Mutação/genética , Tolerância a Radiação/efeitos da radiação , Substituição de Aminoácidos/genética , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/genética , Hipóxia Celular/efeitos da radiação , Linhagem Celular Tumoral , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos da radiação , Relação Dose-Resposta à Radiação , Glioma/enzimologia , Glioma/genética , Humanos , Reação em Cadeia da Polimerase em Tempo Real , Reprodutibilidade dos Testes , Fatores de Tempo , Transdução Genética , Ensaio Tumoral de Célula-TroncoRESUMO
BACKGROUND: Recently antiangiogenic therapy with bevacizumab has shown a high but transient efficacy in glioblastoma (GBM). Indeed, GBM is one of the most angiogenic human tumors and endothelial proliferation is a hallmark of the disease. We therefore hypothesized that tumor cells may participate in endothelial proliferation of GBM. MATERIALS AND METHODS: We used EGFR FISH Probe to detect EGFR amplification and anti-CD31, CD105, VE-cadherin, and vWF to identify endothelial cells. Endothelial and GBM cells were grown separately, labeled with GFP and DsRed lentiviruses, and then cocultured with or without contact. RESULTS: In a subset of GBM tissues, we found that several tumor endothelial cells carry EGFR amplification, characteristic of GBM tumor cells. This observation was reproduced in vitro: when tumor stem cells derived from GBM were grown in the presence of human endothelial cells, a fraction of them acquired endothelial markers (CD31, CD105, VE-cadherin, and vWF). By transduction with GFP and DsRed expressing lentiviral vectors, we demonstrate that this phenomenon is due to cell fusion and not transdifferentiation. CONCLUSION: A fraction of GBM stem cells thus has the capacity to fuse with endothelial cells and the resulting hybrids may participate in tumor microvascular proliferation and in treatment resistance.
Assuntos
Neoplasias Encefálicas/patologia , Células Endoteliais/citologia , Regulação Neoplásica da Expressão Gênica , Glioblastoma/irrigação sanguínea , Neoplasias/patologia , Neovascularização Patológica , Antígenos CD/metabolismo , Caderinas/metabolismo , Diferenciação Celular , Proliferação de Células , Técnicas de Cocultura , Endoglina , Receptores ErbB/genética , Proteínas de Fluorescência Verde/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Hibridização in Situ Fluorescente , Lentivirus/genética , Lentivirus/metabolismo , Microcirculação , Fenótipo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Receptores de Superfície Celular/metabolismoRESUMO
IDH1/2 mutation is the most frequent genomic alteration found in gliomas, affecting 40% of these tumors and is one of the earliest alterations occurring in gliomagenesis. We investigated a series of 1305 gliomas and showed that IDH mutation is almost constant in 1p19q codeleted tumors. We found that the distribution of IDH1(R132H) , IDH1(nonR132H) , and IDH2 mutations differed between astrocytic, mixed, and oligodendroglial tumors, with an overrepresentation of IDH2 mutations in oligodendroglial phenotype and an overrepresentation of IDH1(nonR132H) in astrocytic tumors. We stratified grade II and grade III gliomas according to the codeletion of 1p19q and IDH mutation to define three distinct prognostic subgroups: 1p19q and IDH mutated, IDH mutated--which contains mostly TP53 mutated tumors, and none of these alterations. We confirmed that IDH mutation with a hazard ratio = 0.358 is an independent prognostic factor of good outcome. These data refine current knowledge on IDH mutation prognostic impact and genotype-phenotype associations.
Assuntos
Glioma/genética , Glioma/mortalidade , Isocitrato Desidrogenase/genética , Mutação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 1/genética , Intervalo Livre de Doença , Feminino , Glioma/enzimologia , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estudos Retrospectivos , Taxa de Sobrevida , Proteína Supressora de Tumor p53/genéticaRESUMO
Diffuse intrinsic brainstem gliomas (DIBG) account for 1-2 % of adult gliomas. Their biological characteristics are scarcely understood and whether DIBG are biologically different from supratentorial gliomas remains to be established. We analyzed 17 DIBG samples for IDH1 R132H, alpha internexin, p53, and Ki67 expression, and, in a subset with sufficient DNA amount, for IDH1 and histone H3 mutational status, genomic profiling and MGMT promoter methylation status. A series of 738 adult supratentorial gliomas was used for comparison. Median age at diagnosis was 41 years (range 18.9-65.3 years). Median overall survival was 48.7 months (57 months for low-grade vs. 16 months for high-grade gliomas, p < 0.01). IDH1 sequencing revealed two mutations (IDH1 (R132G) , IDH1 (R132C) ) out of 7 DIBG whereas the R132H IDH1 enzyme was detected in 1/17 DIBG, suggesting that IDH1 mutations are mostly non R132H in DIBG (2/2), in contrast to supratentorial gliomas (31/313; p = 0.01). Mutations in histone genes H3F3A (encoding H3.3) and HIST1H3B (encoding H3.1) were found in 3/8 (37.5 %) of the DIBG (two H3F3A (K27M) and one HIST1H3B (K27M) ) versus 6/205 (2.9 %) of the supratentorial high-grade gliomas (four H3F3A (G34R) and two H3F3A (K27M) ) (p = 0.002). The CGH array showed a higher frequency of chromosome arm 1q gain, 9q gain and 11q loss in DIBG compared to the supratentorial high-grade gliomas, which had a less frequent chromosome 7 gain, and a less frequent chromosome 10 loss. No EGFR amplification was found. These data suggest that adult DIBG differ from adult supratentorial gliomas. In particular, histone genes (H3F3A (K27M) , HIST1H3B (K27M) ) mutations are frequent in adult DIBG whereas IDH1 (R132H) mutations are rare.
Assuntos
Neoplasias do Tronco Encefálico/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioma/genética , Isocitrato Desidrogenase/genética , Mutação/genética , Proteínas Supressoras de Tumor/genética , Adulto , Análise Mutacional de DNA , Feminino , Histonas/genética , Humanos , Proteínas de Filamentos Intermediários/genética , Proteínas de Filamentos Intermediários/metabolismo , Antígeno Ki-67/metabolismo , Perda de Heterozigosidade/genética , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética , Proteína Supressora de Tumor p53/genética , Adulto JovemRESUMO
We have previously identified tagSNPs at 8q24.21 influencing glioma risk. We have sought to fine-map the location of the functional basis of this association using data from four genome-wide association studies, comprising a total of 4147 glioma cases and 7435 controls. To improve marker density across the 700 kb region, we imputed genotypes using 1000 Genomes Project data and high-coverage sequencing data generated on 253 individuals. Analysis revealed an imputed low-frequency SNP rs55705857 (P = 2.24 × 10(-38)) which was sufficient to fully capture the 8q24.21 association. Analysis by glioma subtype showed the association with rs55705857 confined to non-glioblastoma multiforme (non-GBM) tumours (P = 1.07 × 10(-67)). Validation of the non-GBM association was shown in three additional datasets (625 non-GBM cases, 2412 controls; P = 1.41 × 10(-28)). In the pooled analysis, the odds ratio for low-grade glioma associated with rs55705857 was 4.3 (P = 2.31 × 10(-94)). rs55705857 maps to a highly evolutionarily conserved sequence within the long non-coding RNA CCDC26 raising the possibility of direct functionality. These data provide additional insights into the aetiological basis of glioma development.
Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 8 , Glioma/genética , Alelos , Estudos de Casos e Controles , Estudos de Associação Genética , Genótipo , Glioma/patologia , Humanos , Gradação de Tumores , Razão de Chances , Polimorfismo de Nucleotídeo Único , População Branca/genéticaRESUMO
Chromosome arms 1p and 19q codeletion, corresponding to an unbalanced reciprocal translocation t(1;19)(q10;p10), is seen in oligodendroglial tumours and is associated with better prognosis and better chemosensitivity. BRAF abnormalities are observed in pilocytic astrocytomas (tandem duplication-rearrangement) and in pleomorphic xanthoastrocytomas (BRAF V600E mutation). The vast majority of primary or de novo glioblastomas exhibit genetic abnormalities disrupting the intracellular signaling pathways of: transmembrane tyrosine kinase receptors to growth factors and their downstream signaling pathways (i.e. NF1-RAS-RAF-MAPK and PTEN-PI3K-AKT-TSC-mTOR); RB and; TP53. IDH1 and IDH2 mutations are frequent in diffuse grade II and grade III gliomas and in secondary glioblastomas. They are diagnostic and favorable independent prognostic biomarkers. In contrast, they are rare in primary or de novo glioblastomas and not reported in pilocytic astrocytomas. Germlin mutations in MSH2/MLH1/PMS2/MSH6, CDKN2A, TSC1/TSC2, PTEN, TP53 and NF1/NF2 predispose to glial tumors in the setting of hereditary cancer predisposition syndromes. Single nucleotide polymorphisms in TERT,CCDC26, CDKN2A/CDKN2B, RTEL, EGFR and PHLDB1 confer an inherited susceptibility to glial tumors.