Absence of IDH mutation identifies a novel radiologic and molecular subtype of WHO grade II gliomas with dismal prognosis

Abstract

The phenotypic heterogeneity of low-grade gliomas (LGGs) is still inconsistently explained by known molecular abnormalities in patients treated according to the present standards of care. IDH1 codon 132 and IDH2 codon 172 sequencing was performed in a series of 47 LGGs and correlated with clinical presentation, MR imaging characteristics, genomic profile and outcome. A total of 38 IDH1 mutations at codon 132 and 2 IDH2 mutations at codon 172 were found, including 35 R132H (87.5%), 2 R132C (5.0%), 1 R132S (2.5%) and 2 R172 M (5%). The IDH mutations were significantly associated with 1p19q deleted genotype (P = 0.031) and p53 expression (P = 0.014). The presence (vs. absence) of IDH mutations was associated with a better outcome (5-year survival rate, 93% vs. 51%, respectively, P = 0.000001). After adjustment for age, tumor location and size, radiologic infiltration pattern and extent of surgery, multivariate analysis confirmed that IDH mutations was an independent favorable prognostic factor (hazard ratio = 40.9; 95% CI, 2.89-578.49, P = 0.006). Furthermore, we showed that patients with IDH-nonmutated tumors were significantly older (P = 0.020) and that these tumors involved significantly more frequently the insula (P = 0.004), were larger in size (>6 cm, P = 0.047), displayed an infiltrative pattern on MRI (P = 0.007) and were all p53 negative with no 1p19q deletion (P < 10⁻⁶). The absence of IDH mutations in LGGs identifies a novel entity of LGGs with distinctive location, infiltrative behavior, specific molecular alterations, and dismal outcome. These findings could significantly modify the LGG classification and may represent a new tool to guide patient-tailored therapy.

Multimodal MR Imaging (Diffusion, Perfusion, and Spectroscopy): Is It Possible to Distinguish Oligodendroglial Tumor Grade and 1p/19q Codeletion in the Pretherapeutic Diagnosis?

“…15 Chromosomal arms 1p and 19q copy numbers were determined by fluorescence in situ hybridization with locus-specific probes for 1p36 and 19q13, as described elsewhere. 16 No individual investigation of 1p or 19q was considered. …”

TERT promoter mutations contribute to subset prognostication of lower-grade gliomas

“…8 Apart from its use in difficult diagnostic situations, [8][9][10] mutation of this enzyme also stratifies diffuse gliomas prognostically. 11,12 Recently, recurrent mutations in the promoter region of telomerase reverse transcriptase (TERT), the gene encoding catalytic subunit of telomerase, were detected in B70% of malignant melanomas. 13,14 Mutations caused a cytosine-tothymine transition at the positions of chr5, 1 295 228 (C228T) and 1 295 250 (C250T), and generated an identical 11 base-pair nucleotide sequence (5 0 -CCC CTTCCGGG-3 0 ) containing a consensus binding site (5 0 -TTCC-3 0 ) for E-twenty-six transcription factors.…”

Molecular Investigation of Isocitrate Dehydrogenase Gene (IDH) Mutations in Gliomas: First Report of IDH2 Mutations in Indian Patients

“…The difference in the frequency of IDH1 mutation may be attributed to sample size, variable sensitivity of the detection assays, or the racial differences can also be taken into consideration. In contrast to IDH1 mutations, IDH2 mutations in gliomas appear to be less frequent with reported incidence ranging between 0.9-4.2% Metellus et al, 2010;Qi et al, 2011;Musaka et al, 2012). Infact, in the current study none of the cases revealed any mutations in IDH2, which is in agreement with previous report (Krell et al, 2011), thereby further suggesting that IDH2 mutations are rare in gliomas.…”

“…In contrast IDH2 mutations are rare, but more common in oligodendroglial tumors, as compared to astrocy¬tomas (Raynaud et al, 2010 protective mechanism in glioma patients which could be the reason for better outcome in patients with mutant IDH than those with the wild-type IDH genes (Zhu et al, 2011). Most of the available studies on IDH1 and 2 mutations are reported from western countries (Bleeker et al, 2009;Metellus et al, 2010;Van den Bent et al, 2010;Cykowski et al, 2012), few reports from Asia (Mukasa et al, 2012;Song Tao et al, 2012), while there is only one report of IDH1 mutations in Indian glioma patients (Jha et al, 2011). In the current study we evaluated IDH1 and IDH2 mutations in glioma patients of different histological types and grades with the aim of assessing their frequency, distribution pattern and their correlation with clinicopathological findings.…”