Genetic Testing in Glioblastoma and Brain Tumours: What It Means and Why It Matters
In this series of articles based on the final report of the Sixth Biennial World Summit of Brain Tumour Patient Advocates organised by the IBTA in Rome in November 2025, we turn to one of the topics most directly relevant to anyone who has just received a diagnosis: genetic testing. The subject was presented at the Summit by Professor Manfred Westphal from the University of Hamburg, one of the world’s leading experts in brain tumour surgery.
When you are diagnosed with a brain tumour, the pathology report today does not simply say “glioblastoma” or “astrocytoma”. It also lists a series of abbreviations and mutations — IDH, MGMT, H3K27-M, BRAF — that at first glance seem incomprehensible. Yet those abbreviations are not technical details for doctors alone: they are the key used to decide your treatment, estimate your prognosis, and assess your eligibility for certain therapies or clinical trials. Understanding what they mean — at least in broad terms — is a practical tool for patients and those close to them.
Until not many years ago, brain tumours were classified mainly on the basis of how cells looked under a microscope (histology). It was then discovered that two tumours appearing identical under the microscope can behave in completely different ways — one responds to treatment, the other does not — simply because they have different molecular profiles. This led to what is now called integrated diagnosis: the classification of a tumour is no longer based on histology alone, but on the combination of morphological and molecular characteristics. The World Health Organisation updated its classification of brain tumours precisely in this direction, and the European guidelines (EANO) for the treatment of gliomas are now based on these molecular parameters.
IDH stands for isocitrate dehydrogenase, an enzyme involved in cellular metabolism. When the gene encoding it is mutated, the cell produces an abnormal substance (2-hydroxyglutarate) that disrupts the regulation of DNA and promotes tumour transformation. The presence or absence of the IDH mutation is today one of the main criteria for classifying gliomas. IDH-mutant gliomas tend to follow a slower course and carry a better prognosis than IDH wild-type gliomas (those without the mutation). Glioblastoma in adults is in most cases IDH wild-type — this is one of the factors that makes it so aggressive. Astrocytomas and oligodendrogliomas of grade 2 and 3 are frequently IDH-mutant. The practical relevance is concrete: vorasidenib, an oral inhibitor of IDH1 and IDH2 mutations, has recently been approved by the EMA for the treatment of grade 2 IDH-mutant oligodendrogliomas and astrocytomas. It is the first targeted treatment approved specifically for low-grade gliomas in Europe. Without genetic testing, there would be no way of knowing who should receive it.
Another marker of great importance — particularly for those facing glioblastoma — is the methylation status of the MGMT promoter. MGMT (O6-methylguanine-DNA methyltransferase) is an enzyme that repairs DNA damage caused by certain chemotherapy drugs, in particular temozolomide, the standard chemotherapy agent in the treatment of glioblastoma. When the MGMT gene promoter is methylated — meaning a chemical modification effectively “switches off” the gene — the tumour cell can no longer repair the damage produced by temozolomide, making the drug more effective. In practice, MGMT promoter methylation is the main predictive marker of response to temozolomide chemotherapy: patients with MGMT-methylated glioblastoma tend to respond better to standard treatment and generally have a more favourable prognosis than those with unmethylated MGMT. Approximately 40–50% of glioblastomas carry this characteristic. For this reason, knowing the MGMT promoter methylation status is not a minor detail — it is one of the first things to ask your doctor after diagnosis.
The H3K27-M mutation primarily affects diffuse midline gliomas — tumours that develop in deep brain structures such as the brainstem, thalamus, or spinal cord. These are particularly difficult to treat, both because of their location and their biological aggressiveness. The abbreviation refers to a specific modification of histone protein H3 (substitution of lysine with methionine at position 27), which alters the way DNA is “packaged” within the cell and erroneously activates genes that promote tumour growth. Dordaviprone is a drug developed specifically for tumours harbouring this mutation: it has shown efficacy in recurrent H3K27-M positive tumours and is now under investigation for newly diagnosed cases as well.
The BRAF mutation involves a gene responsible for transmitting cell growth signals. In brain tumours it is found mainly in certain paediatric and young adult gliomas, but it can also appear in adult tumours. Its relevance lies in the existence of drugs specifically developed to block it: tovorafenib, a type II BRAF inhibitor, is currently under investigation for brain tumours carrying this mutation and is showing promising results. Identifying a BRAF mutation in the genetic report therefore opens the door to potentially effective targeted therapies.
Genetic testing on a brain tumour can be performed using several methods, often in combination. DNA sequencing analyses the genetic sequence of the tumour sample to identify mutations, amplifications, or deletions of specific genes. Mutation-specific immunohistochemistry uses antibodies to detect the presence of abnormal proteins produced by mutated genes: it is faster and less costly than sequencing, but only identifies mutations for which a specific antibody exists. Epigenetic methylation profiling analyses patterns of DNA methylation — chemical modifications that regulate gene expression without altering the sequence itself — and is the tool used, among other things, to determine MGMT promoter methylation status. The sample on which these tests are performed is normally the tumour tissue removed during surgery or biopsy: this is why the quality and quantity of the surgical sample matter not only for histological diagnosis, but also for molecular analysis.
One of the most interesting frontiers is liquid biopsy: the idea of searching the blood or cerebrospinal fluid for traces of the tumour — circulating tumour DNA fragments, abnormal metabolites, tumour cells — without the need for tissue sampling. It would be a valuable tool for monitoring disease progression over time, assessing treatment response, and detecting recurrence early. At present, the detection of certain mutations such as H3K27-M and 2-hydroxyglutarate (a marker of IDH mutations) in plasma or cerebrospinal fluid appears technically feasible. Detection of IDH mutations themselves remains more challenging. Liquid biopsy for brain tumours is not yet a routine clinical tool, but research in this field is very active.
If you have received a diagnosis of glioblastoma or a brain tumour, some concrete questions to ask your neurologist or neuro-oncologist: has my tumour been tested for IDH, BRAF, and H3K27-M? What is the MGMT promoter methylation status? Does my molecular profile make me eligible for targeted therapies or clinical trials? Does the pathology report include an integrated diagnosis according to the updated WHO classification? Knowing the genetic signature of your tumour does not change the emotional journey of the illness. But it can open therapeutic doors that might otherwise remain closed.
Source: Report of the Sixth Biennial World Summit of Brain Tumour Patient Advocates, IBTA, Rome, 2–5 November 2025. Presentations by Prof. Manfred Westphal (University of Hamburg) and Prof. Riccardo Soffietti (CancerSucks APS, Turin).
