Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Glioblastoma [C71.-]

OMIM numbers: 137800MGMT (156569), IDH1 (147700), IDH2 (147650), TP53 (191170)

Dipl.-Ing. (FH) Tanja Hinrichsen,
Prof. Dr. med. Barbara Dockhorn-Dworniczak

Scientific Background

Glioblastoma is the most common and aggressive astrocytic tumor. Glioblastoma accounts for more than half of all gliomas and usually occurs in the cerebrum of adults, with the peak age between 45 and 70 years. Most glioblastomas emerge with a short clinical history (primary glioblastoma). Secondary glioblastomas develop from a pre-existing diffuse or anaplastic astrocytoma. The prognosis is unfavorable despite intensive therapy. Standard treatment, operation followed by radiotherapy in addition to chemotherapy with temozolomide, increases the median survival to 12-15 months. However, with modern chemotherapy, survival of more than 3 years from diagnosis is increasingly seen, especially in younger patients.

Mutations in IDH1 whilst rare in primary glioblastoma (10%) are common in secondary glioblastoma (80%) and are consequently a molecular marker for secondary glioblastoma. These tumors are usually associated with a better prognosis. In addition, 3% of glioblastomas show mutations in IDH2, which indicates an oligodendroglial origin. IDH mutated glioma have a particular clinical phenotype: patients are significantly younger than those with IDH wild-type glioma and often present with localization in the frontal lobe as well as a larger tumor at the time of diagnosis. Furthermore, TP53 mutations, 1p/19q deletions and MGMT promotor methylation are associated with the disease. Mutations in IDH1 usually affect codon 132 and those in IDH2 affect codon 172. The presence of a mutation can also have potential as a therapeutic target. Thus AGI 5198 is directed against IDH1 R132H mutations and AGI 6780 against IDH2 R140Q mutations.

The above mentioned survival advantage given by a combination of radiotherapy and temozolomide chemotherapy primarily concerns patients whose tumors show MGMT promoter methylation. Temozolomide is an alkylating cytostatic medication, that causes a G2/M arrest, mismatches and consequently apoptosis through the addition of a methyl group at the O6 position of guanine in DNA.  MGMT is an O6-methylguanine DNA methyltransferase and a so-called suicidal DNA repair protein, that induced by temozolomide methylation can remove DNA damage, by catalyzing the transfer of the O6 position inserted methylguanine to a cysteine residue at its own position 145. If there is already a methylation in the MGMT promoter, which is the case in approximately 40% of patients, the gene is shut down and MGMT switched off. Therefore, existing MGMT promoter methylation is positive for combined radiotherapy and temozolomide chemotherapy. Secondary resistance to temozolomide can be caused by point mutations in TP53 and other genes of the DNA mismatch repair system.