Abstract
IDH mutational status is required for proper diagnosis according to the WHO criteria revised in 2016. The single nucleotide polymorphism (SNP) rs11554137 (IDH1105GGT) at codon 105 of IDH1 has been reported in patients with several tumor types, including those with glioma. The aim of this study is to investigate the prevalence of IDH1105GGT in a cohort of brain tumors, and its association with clinicopathologic features and IDH1 and IDH2 missense mutations. Exon 4 of IDH1 and IDH2 was analyzed in a series of brain tumors classified according to current WHO criteria. DNA from control individuals was analyzed to infer the prevalence of IDH1105GGT in the reference population. Analysis was performed using next generation sequencing. IDH1105GGT was three times more frequent in patients with tumors (44/293 cases, 15.0%) vs. population controls (6/109, 5.5%) (p = 0.0102). IDH1105GGT was more frequent in grade III tumors (26.1%) compared to grade II (10.9%, p = 0.038) and grade IV tumors (13.7%, p = 0.041). IDH1105GGT was more frequent in grade II and III tumors without an IDH tumor missense mutation (43.8%) than in those with (11.5%, p = 0.005). The IDH1105GGT SNP likely represents an important genetic marker, worthy of additional investigation to better understand the clinical and biological features of IDH-WT infiltrating gliomas.
Highlights
The isocitrate dehydrogenase (IDH) family includes three isozymes (IDH1, IDH2, IDH3) involved in the Krebs cycle as active participants in NADPH production
In all but two patients harboring IDH1105GGT, the single nucleotide polymorphism (SNP) was detected in about 50% of alleles analyzed, a frequency that is fully compatible with a heterozygous germline event
In our Italian cohort, the prevalence of the IDH1105GGT SNP was considerably higher in patients with brain tumors compared to the control population (15.5% vs 5.5%, respectively)
Summary
The isocitrate dehydrogenase (IDH) family includes three isozymes (IDH1, IDH2, IDH3) involved in the Krebs cycle as active participants in NADPH production These proteins play an important role in the cellular control of oxidative damage[1,2]. The SNP (p.G105G, rs11554137:C > T -IDH1105GGT, minor allele frequency 0.0569) has since been frequently reported in AML and is linked to an adverse prognosis[26,27,28] It has been reported in brain tumors in a study of patients with gliomas (grade II to IV) from France and Germany[29] and in a series of Bulgarian GBM patients[30], as well as in thyroid tumors (both carcinomas and adenomas)[9,10]. The role and biologic significance of the IDH1105GGT SNP in tumorigenesis is poorly understood, but it appears to be associated with increased IDH1 mRNA levels leading to altered NADPH production[25,29]
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