BACKGROUND:The IDH1 gene, which encodes isocitrate dehydrogenase 1, is frequently mutated in gliomas and acute myeloid leukemia. The single-nucleotide polymorphism (SNP) (reference SNP no. rs11554137:C>T) located on IDH1 codon 105 has been associated with a poor outcome in patients with acute myeloid leukemia but has not been investigated in patients with gliomas. METHODS:The IDH1 codon 105 SNP was genotyped first in a series of 952 patients with grade 2 through 4 gliomas and was correlated with outcomes and tumor genomic profile. Then, it was genotyped in 2 validations sets of 306 patients with glioblastoma (GBM) and 591 patients with glioma. RESULTS:The minor allele codon 105 glycine (GGT) SNP (IDH1(105GGT) ) was identified in 98 of 952 patients (10.3%) and was not associated with the codon 132 (IDH1(132) ) mutation. Patients who had GMB with the IDH1(105GGT) variant had a poorer outcome than patients without the variant (median overall survival [OS], 10.7 months vs 15.5 months; P = .001; median progression-free survival [PFS], 6.4 months vs 8.5 months; P = .003). The prognostic impact was confirmed in an independent validation set of 306 GBMs from the same center (median PFS, 6.8 months vs 9.7 months; P = .006; median OS, 13.9 months vs 18.8 months; P = .0187). In the second validation cohort (591 grade 2-4 gliomas), a significant association was observed between IDH1(105GGT) and an adverse prognosis for the overall series and for patients with World Health Organization grade 3 gliomas, but the difference did not reach significance in patients with GBM. CONCLUSIONS:Taken together, the current data strongly suggested an association between the SNP rs11554137:C>T polymorphism and adverse outcomes in patients with malignant glioma. A single-nucleotide polymorphism (SNP) located on codon 105 of the isocitrate dehydrogenase 1 (IDH1) gene (reference SNP rs11554137) is analyzed in 3 independent series of patients with gliomas. The SNP rs11554137 is independent of the occurrence of somatic mutation on IDH1 codon 132, but, per se, has a prognostic impact in malignant gliomas.

译文

背景:编码异柠檬酸脱氢酶1的IDH1基因在神经胶质瘤和急性髓细胞性白血病中经常发生突变。位于IDH1密码子105上的单核苷酸多态性(SNP)(参考SNP号rs11554137:C> T)与急性髓细胞性白血病患者的不良预后相关,但尚未在神经胶质瘤患者中进行过研究。
方法:IDH1密码子105 SNP首先在一系列952例2至4级神经胶质瘤患者中进行基因分型,并与预后和肿瘤基因组特征相关。然后,在306例胶质母细胞瘤(GBM)患者和591例胶质瘤患者的2个验证组中对其进行了基因分型。
结果:在952名患者中的98名(10.3%)中鉴定出次要等位基因105甘氨酸(GGT)SNP(IDH1(105GGT)),与132号密码子(IDH1(132))突变无关。具有IDH1(105GGT)变体的GMB患者比没有该变体的患者的预后较差(中位总生存期[OS]为10.7个月vs 15.5个月; P = .001;中位无进展生存期[PFS]为6.4个月) vs 8.5个月; P = 0.003)。在来自同一中心的306个GBM的独立验证集中确认了预后影响(中位PFS,6.8个月对9.7个月; P = .006;中位OS,13.9个月对18.8个月; P = .0187)。在第二个验证队列(591个2-4级神经胶质瘤)中,观察到IDH1(105GGT)与整个系列以及世界卫生组织3级神经胶质瘤患者的不良预后之间存在显着相关性,但差异没有显着性在GBM患者中。
结论:综上所述,当前数据强烈表明SNP rs11554137:C> T多态性与恶性神经胶质瘤患者不良预后之间存在关联。在3个独立的神经胶质瘤患者系列中分析了位于异柠檬酸脱氢酶1(IDH1)基因(参考SNP rs11554137)密码子105上的单核苷酸多态性(SNP)。 SNP rs11554137与IDH1密码子132上体细胞突变的发生无关,但就其本身而言,对恶性神经胶质瘤具有预后影响。

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