Читать книгу Intracranial Gliomas Part II - Adjuvant Therapy - Группа авторов - Страница 24

Mutations of IDH1/IDH2 were first identified in 2008 in approximately 70–80% of WHO grade II and III astrocytic and oligodendroglial tumors, and in a subset of GBM [41, 42]. Among astrocytomas this molecular alteration is slightly more common in WHO grade II (59–90% of cases) as compared to WHO grade III (28–82% of cases) lesions [14]. Circumscribed astrocytomas as well as ependymal, neuronal, and mixed neuronal-glial (e.g., ganglioglioma) neoplasms, practically never demonstrate this genetic abnormality, which is also not seen in non-neoplastic mimickers of gliomas [6, 13, 42, 43]. Mutation of IDH1 at codon R132H (IDH1^R132H) is most frequent and makes up 70–96% of cases [4, 5, 8, 22, 44]. Of interest, for unknown reasons all astrocytomas in patients with Li-Fraumeni syndrome (linked to germline TP53 mutations) carry a different IDH1 mutation (IDH1^R132C). HGG in young adults are more likely to carry mutant IDH1/IDH2, than those in the elderly [5, 13], while the opposite trend was noted in the isolated cohort of LGG [22].

IDH1 encodes a cytosolic protein and IDH2 its mitochondrial analogue, both of which work as enzymes that produce CO₂ and α-ketoglutarate through oxidative decarboxylation of isocitrate [13, 37]. Their mutations result in novel enzymatic activity with preferential affinity to α-ketoglutarate instead of isocitrate, resulting in production and accumulation of D-2-hydroxyglutarate [14]. The latter is an oncometabolite that plays a central role in the pathogenesis of various cancers, including gliomas, particularly through alteration of DNA demethylation and gene transcription [14, 37]. Additionally, IDH1/IDH2 mutations may result in decreased formation of NADPH (reduced form of nicotinamide adenine dinucleotide phosphate), leading to DNA oxidation, overwhelming of its repair mechanisms, and eventually producing irreversible damage [37]. At present a commercially available antibody against IDH1^R132H-mutant protein allows highly specific IHC analysis of formalin-fixed paraffin-embedded tumor tissue demonstrating strong cytoplasmic staining of the neoplastic cells harboring the mutation [44–46]. Relying on direct sequencing of PCR (polymerase chain reaction) products as a “gold standard,” IHC provides 90% sensitivity, 100% specificity, 100% positive predictive value (PPV), and 95% negative predictive value (NPV) for identification of IDH1^R132H mutations [5]. Monoclonal antibodies for identification of other types of IDH1/IDH2 mutations also exist, with the exception of IDH1^R132C [14, 46]. If molecular characterization is critical for clinical decision-making, another testing method should be applied in immunonegative cases; in particular, Sanger sequencing provides accurate diagnostic information if the tissue specimen contains a sufficient number of tumor cells [44].

In isolation IDH1/IDH2 mutations are encountered in gliomas only infrequently (13–17% of WHO grade II tumors [22, 38]), and they are often associated with other genetic abnormalities. Such mutations were identified along with mutations of TP53 and ATRX in 60–70% of diffusely infiltrating astrocytomas, and with 1p/19q co-deletion in more than 90% of “classic” OD/AOD [7, 47]. In pediatric and adult HGG IDH1/IDH2 mutations are mutually exclusive with H3 alterations [17].

Multiple studies have demonstrated the prognostic and predictive benefits of IDH1/IDH2 mutations through all histopathological types and grades of diffusely infiltrating gliomas [9, 12, 36, 37, 48]. IDH1 mutation was revealed as the most prominent isolated prognostic factor in a combined set of AA and pGBM, followed by age, histology, and MGMT promoter methylation status [5]. SongTao et al. [34] showed that the presence of IDH1 mutation predicts longer survival and better response of sGBM to chemotherapy with temozolomide (TMZ). Moreover, tumors carrying IDH1/IDH2 mutations may be more amenable to gross total surgical resection [37]. Even lower-grade IDH wild-type gliomas frequently demonstrate an aggressive clinical course and are associated with dismal prognosis [7, 13, 38]. Hartmann et al. [5] revealed that IDH1 wild-type AA are associated with worse outcome not only in comparison with their mutant counterparts, but also with GBM carrying this genetic abnormality. However, the presence of wild-type IDH in diffusely infiltrating WHO grade II and III gliomas may not be invariably linked to less favorable prognosis, unless the tumor carries other glioblastoma-like molecular alterations.