IDH1 and IDH2 mutations, immunohistochemistry and associations in a series of brain tumors

Abstract

A total of 343 brain tumors were studied for IDH1 and IDH2 mutations by direct sequencing and for protein expression by immunohistochemistry with mIDH1(R132H) antibody. Of these, 287 were gliomas (17 pilocytic astrocytomas, 13 grade II and 5 grade III astrocytomas, 167 primary (pGBMs) and 19 secondary (sGBMs) glioblastomas, 36 grade II and 26 grade III oligodendrogliomas and 4 grade II-III oligoastrocytomas). In gliomas, IDH1 mutations at codon R132 were identified in 22.3%, of which 93.7% were c.395G>A (p.R132H). Mutations were more frequent in oligodendrogliomas (53.2%) than in astrocytic tumors (22.8%) and in sGBMs (84.2%) upon pGBMs (1.8%). There was a statistically significant correlation between mIDH1(R132H) antibody immunostaining and the relevant mutation c.395G>A (p.R132H) (P = 0.0001). No mutations were identified in non-glial tumors which were also negative to immunohistochemistry, with the exception of one PNET. A c.515G>T (p.R172M) mutation of the IDH2 gene was only identified in a grade II oligodendroglioma patient which was wild-type for IDH1. A direct correlation with MGMT promoter hypermethylation status and an inverse correlation with EGFR amplification was found, whereas the relationships with 1p/19q co-deletion and TP53 mutations only showed a trend toward correlation. In all gliomas, a positive correlation was found between IDH1 mutations and a young age (P = 0.0001). In contrast, a correlation with overall survival could only be obtained in low-grade gliomas. Immunohistochemistry appeared to be useful in differential diagnoses, especially toward non-tumor pathologic nervous tissue, and in recognizing infiltrating glioma cells. The mIDH1(R132H) antibody positivity was complementary with Cyclin D1 expression.

Genetic alterations of IDH1 and Vegf in brain tumors

“…Here we report the genetic variables in a Spanish cohort of patients with brain tumors, which presents a distribution of gliomas similar to other studies previously published in other countries (Lewandowska et al., 2014; Mellai et al., 2011; Reuss et al., 2015; Thota et al., 2012) with the exception of the low number of WHO grade III tumors available on this study. From a clinical point of view, there were two clinical parameters that showed differences between primary and secondary cohorts, both related to the better outcome of primary tumors.…”

“…Thus, this gene is strongly involved in the biology of gliomagenesis (Ducray et al., 2011; Takano et al., 2012). The IDH1 gene may be the key in the pathogenic processes associated with the R132H mutation and those caused by the accumulation of R2‐HG (Ducray et al., 2011; Mellai et al., 2011; Parsons et al., 2008; Thota et al., 2012; Weller et al., 2009). This accumulation produces a high intracellular metabolic stress, so cells need to get adapted to this condition to facilitate survival and tumor progression (Van Lith et al., 2014).…”

“…This accumulation produces a high intracellular metabolic stress, so cells need to get adapted to this condition to facilitate survival and tumor progression (Van Lith et al., 2014). Previous studies reported a 22–70% of IDH1 R132H mutation frequency (Ducray et al., 2011; Lewandowska et al., 2014; Mellai et al., 2011; Reuss et al., 2015; Thota et al., 2012). In our study, the frequency of this mutation is lower, 15%; these differences might be due to the presence of a smaller number of patients in WHO grade III primary gliomas and grade IV secondary gliomas.…”

“…However, R132H mutation distribution is in accordance with previous studies. Mutation has not been described in WHO grade I astrocytoma but appears in 100% of ODGs and not in meningiomas and other primary tumors (Lewandowska et al., 2014; Mellai et al., 2011; Takano et al., 2012; Table 2). Sanson et al.…”

“…IDH1 R132H mutation overexpression has been shown to decrease cell proliferation (Parsons et al., 2008). Several studies show the presence of the IDH1 R132H mutation in 70–90% of secondary GBMs and 10% primary GBMs, both cases associated with young patients and a higher overall survival rate (Bleeker et al., 2012; Carrillo et al., 2012; Mellai et al., 2011; Weller et al., 2009). The median survival of patients with IDH1 mutation is 3.8 years compared with 1.1 years in patients with wild‐type IDH1 (Parsons et al., 2008).…”