Gliomas (astrocytomas, oligodendrogliomas and glioblastomas) are the most common primary brain tumors in adults, accounting for approximately 50% of all cases.
GENOMIC ALTERATIONS
First, a biological and prognostic classification of WHO grade II to III gliomas is performed based on the occurrence of somatic variants in the genes IDH1 and IDH2. Pathogenic variants in IDH1 and IDH2 can be detected in over 70% of primary astrocytomas, oligodendrogliomas and secondary glioblastomas. Thus, the absence of variants in IDH1 and IDH2 in glioblastoma is associated with primary glioblastoma. IDH-altered gliomas also have their own clinical phenotype: patients are significantly younger than those with IDH wild-type gliomas, and often have localization in the frontal lobe and a larger tumor at the time of diagnosis. Tumors with pathogenic variants in IDH1 and IDH2 are also associated with a more favorable prognosis than tumors with IDH1/2 wild-type gliomas.
A further prognosis can now be made based on the presence of a LOH 1p/19q. This depends on the presence or absence of pathogenic variants in the genes IDH1 or IDH2, as well as the loss of heterozygosity (LOH) of 1p/19q. Oligodendrogliomas with a variant in IDH1 or IDH2 and the presence of LOH 1p/19q (approximately 30% of WHO grade II-III gliomas) have the most favorable prognosis. Astrocytomas (approximately 50% of WHO grade II-III gliomas) and WHO grade IV glioblastomas with a variant in IDH1 or IDH2 and the presence of intact 1p/19q have an intermediate prognosis. An unfavorable prognosis is reported for astrocytomas, WHO grade IV diffuse midline glioma with histone H3 Lys27Met variant (approximately 20% of WHO grade II-III gliomas), and WHO grade IV glioblastomas with IDH1/2 wild-type and presence of intact 1p/19q.
POSSIBLE THERAPIES
About 40% of IDH1/2 wild-type glioblastomas show MGMT promoter methylation. Temozolomide is an alkylating cytostatic agent that induces G2/M cell cycle arrest, mismatching and thus apoptosis by adding a methyl group to the O6 position of guanine in the DNA. MGMT is an O6 methylguanine DNA methyltransferase and a so-called suicide DNA repair protein that can reverse temozolomide-induced methylation and thus DNA damage. It does this by catalyzing the transfer of the methyl group inserted at the O6 position of guanine to the cysteine residue of its own position 145.
If methylation is now present in the MGMT promoter gene silencing occurs and MGMT is switched off. Therefore, MGMT promoter methylation positively indicates combined radiotherapy and temozolomide chemotherapy. Secondary resistance to temozolomide can be caused by variants in TP53 and other genes of the DNA mismatch repair system.
TERT variants are found in approximately 72% of IDH wild-type glioblastomas and 26% of IDH mutant glioblastomas. These are often Cys228Thr and Cys250Thr variants of the promoter region. TERT promoter variants are associated with low survival and resistance to radiotherapy.
About 50% of glioblastomas show EGFR alterations (amplification, rearrangement or single nucleotide variant). Nearly 20% of primary glioblastomas have a deletion of exons 2 to 7, EGFRvIII, which is associated with EGFR amplification. Patients in therapy studies are first tested for EGFR amplification or immunohistochemically for EGFRvIII positivity.
TARGETED PANEL
IDH1, IDH2, TERT promotor, MGMT promotor methylation, Fusion Genes: NTRK1/2/3, MSI
