RESUMO
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.
Assuntos
Neoplasias Encefálicas/genética , Glioma/genética , Penetrância , Polimorfismo de Nucleotídeo Único , Proteína Supressora de Tumor p53/genética , Neoplasias Encefálicas/epidemiologia , Estudos de Casos e Controles , Europa (Continente)/epidemiologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Glioma/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/fisiologia , Processamento de Terminações 3' de RNA/genética , Proteína Supressora de Tumor p53/fisiologia , Estados Unidos/epidemiologiaRESUMO
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.
