Molecular Markers

If you have had a biopsy or resection, your doctor may send your tumour tissue for genetic testing to identify any relevant molecular markers, or biomarkers

Molecular markers are genetic features found in your tumour DNA that can

  • help diagnose your tumour

  • predict how fast your tumour might grow

  • guide treatment options, including chemotherapy, radiotherapy or targeted therapies

  • help identify clinical trials that might be relevant to you

Diagnosis

Traditionally brain tumours have been diagnosed by a pathologist looking at the cells under a microscope (histopathology) to determine the cell type and tumour grade. However in some cases it can be difficult to interpret the histology accurately, as some tumour types can appear very similar under the microscope. A more accurate diagnosis can be made if the molecular markers can be identified using a number of different methods of genetic testing. In 2016, the World Health Organisation (WHO) revised their classification of brain tumours to include molecular markers.

Prognosis

The genetic profile of your tumour can help doctors predict how it might respond to particular treatments, for example chemotherapy or radiotherapy. Depending on the type of tumour you have, and which molecular markers are found, doctors may consider the possibility of targeted treatments or participation in a clinical trial. Many new treatments under development are based on targeted therapies, so-called because they target certain molecular markers. Some people may prefer not to know too much about their tumour and how it might predict their prognosis, and that is fine as it comes down to personal choice.

Disadvantages

It is important to note that there are some disadvantages with genetic testing of tumours. Some of these include:

  • Testing of molecular markers is not fool proof and can throw up false positives or negatives.

  • The tissue sample being tested might not represent the whole tumour (tumour heterogeneity).

  • Some people’s tumours might respond differently to the how the genetic test result predicts.

  • Some molecular markers can change in response to treatment, which means the genetic profile of a recurrent tumour following treatment may be different to that of the original tumour.

  • As it is a relatively new practice, genetic testing may not be available in all hospitals.

Common Molecular Markers in Brain Tumours

Below are some of the common molecular markers which doctors test for in New Zealand. It is important to note that not all of these, and perhaps none of them, may be relevant to your tumour.

IDH1 and IDH2 Mutations

  • Isocitrate Dehydrogenase 1 and 2 (IDH1 and IDH2) are metabolic enzymes.

  • Mutations in the genes that produce these enzymes can lead to the production of D-2-hydroxyglutarate, a metabolite that is linked to the development of tumours.

  • Tumours that have these mutations are called “IDH-mutant”. Tumours that don’t have these mutations are known as “IDH-wildtype”.

  • IDH mutations are a hallmark of low-grade gliomas. They are important in defining WHO grade 2 and 3 astrocytomas and oligodendrogliomas.

  • When observed in high-grade gliomas such as glioblastoma (GBM), IDH mutations suggest evolution from a lower grade tumour (secondary GBM).

  • IDH-wildtype tumours are typically associated with primary glioblastomas (primary GBM).

  • IDH-mutant tumours are associated with a relatively favourable prognosis than IDH-wildtype.

1p/19q Codeletion

  • This test is essential for the diagnosis of oligodendroglioma

  • 1p and 19q refers to the p section on chromosome 1 and the q section on chromosome 19. In some tumours, these sections are both missing, or codeleted.

  • Tumours with both an IDH mutation and 1p/19q codeletion are diagnosed as oligodendrogliomas.

  • Tumours with 1p/19q codeletion are more sensitive to radiotherapy and chemotherapy and have a better prognosis than tumours without the codeletion.

MGMT Promoter Methylation

  • This test helps doctors predict who might respond better to chemotherapy and, depending on your tumour type, can help in deciding your preferred treatment options.

  • It is most often used in the treatment planning of glioblastoma (grade 4), anaplastic astrocytoma (grade 3) and anaplastic oligodendroglioma (grade 3) tumours.

  • MGMT, short for O6-methylguanine-DNA methyltransferase, is a DNA repair enzyme that reverses the damage caused by temozolomide and nitrosourea-based chemotherapy.

  • When the promoter region of the MGMT gene is switched off (methylated) the enzyme is absent, making the chemotherapy more effective.

  • An MGMT promoter region which is switched on (unmethylated) results in resistance to chemotherapy.

  • In summary, MGMT methylated tumours respond better to chemotherapy and carry a more favourable prognosis than MGMT unmethylated tumours.

ATRX Mutation

  • This test can help confirm the diagnosis of some types of gliomas such as IDH-mutant astrocytomas and glioblastomas.

  • ATRX mutations in glioma are strongly associated with IDH mutations and are nearly always mutually exclusive with 1p/19q codeletion.

  • An ATRX mutation, coupled with IDH mutation, is typical of astrocytoma.

  • ATRX mutations are not seen in oligodendroglioma or glioblastoma.

TERT Mutation

  • The TERT gene produces an enzyme called telomerase, which is responsible for maintaining the length of telomeres (sections of DNA at the end of chromosomes) in dividing cells.

  • TERT mutations result in overproduction of telomerase which can accelerate tumour growth.

  • When found in 1p/19q codeleted and IDH-mutant tumours, the TERT mutation suggests a diagnosis of oligodendroglioma, and infers greater sensitivity to radiotherapy and chemotherapy.

  • When found in IDH-wildtype tumours, this suggests a diagnosis of glioblastoma, where the TERT mutation is associated with poorer survival.

H3K27M Mutation

  • The H3K27M mutation is the most common of a group of histone H3 gene mutations found in diffuse midline gliomas of children and young adults.

  • The presence of an H3K27M mutation is evidence of an infiltrative glioma.

  • Tumours with H3K27M mutations are typically seen to have a poor prognosis.

BRAF Mutation

  • There are two BRAF mutations of interest in brain tumours – BRAF fusion and the BRAF V600E mutation.

  • The presence of a BRAF fusion is reliable evidence that the tumour is a pilocytic astrocytoma (a type of grade 1 tumour)

  • BRAF V600E mutations can occur in a variety of tumours across all four WHO grades, and may respond to BRAF inhibitors such as vemurafenib.

CDKN2A/B Homozygous Deletion

In the grading of IDH-mutant astrocytomas, homozygous deletion of the CDKN2A/B gene leads to a WHO classification of grade 4, irrespective of microvascular proliferation or necrosis.

There are other molecular markers which may be relevant to your tumour. Many of these are still experimental and require further research to verify their value in clinical practice. If your hospital does not offer genetic testing of all of the relevant biomarkers, there is an option to get this testing done privately. You should consult your specialist to see if this might be a good option for you.