Molecular Markers: Fingerprinting Brain Tumors

Posted on May 29, 2017

Most Filipinos believe that having a brain tumor confers a dismal prognosis. This belief is unhealthy because it overgeneralizes and eliminates the possibility that many brain tumors are treatable. Since the past decade, we have been better at detecting tumors. The discovery of more sensitive diagnostic imaging, efficacious chemotherapeutic agents, targeted radiation modalities, and safe neurosurgical techniques have translated not only to longer survival but also for cure for many of our Filipino brain tumor patients.

In the 1920s, Harvey Cushing and Percival Bailey started the movement to understand brain tumors. They perceived that better classification systems would not only aid prognostication but also lay the foundations for better treatment. These brain tumor classification systems of the World Health Organization (WHO) have evolved through time – as studies showed how tumors behave.

Over the years, it is interesting to note that we saw differences on how tumors behave even if they were under the same classification. With the advent of molecular biology and biotechnology, this raised the theory that brain tumors that have the same histology under the microscope may have distinct molecular “fingerprints”. Scientists think that this method of classification could be more accurate – it will aid us in better understanding these tumors and in modifying treatment to increase the chances of survival and cure.

The discovery of these molecular “fingerprints” or markers over the last two decades has generated renewed interest in the classification of brain tumors. In 2014, revisions to the classification system of brain tumors incorporated molecular findings in brain tumor diagnosis. This resulted in a new classification of brain tumors by the WHO last 2016.

The presence of markers are linked to better treatment response, to prolonged survival even prior to treatment, and to confirmation of the histopathologic diagnosis. Markers also predict the tendency of low-grade tumors to mutate or progress into higher grade malignancies. These markers also influence the choice of therapy and response. These molecular tumor markers have been the mainstay of clinical trials for therapy for brain tumors and evidence has also shown their utility in diagnosis and prognostication. The following markers have led significant benefits for our brain tumor patients:

1. Isocitrate Dehydrogenase 1 (IDH-1) is an important enzyme in the conversion of carbohydrates to energy in the human body. Mutations in the gene encoding for IDH-1 have been found in several primary brain tumors (type of tumors arising exclusively from the brain and spinal cord) including Astrocytoma, Oligodendroglioma and Glioblastoma. Changes brought about by mutation in this gene lead to activation of tumor cells and deactivation of proteins which protect the body from tumors (tumorsuppressor gene). The presence of this type of mutation is found more often in younger patients and confer longer survival and better prognosis.

2. Deletion of the short arm of chromosome 1 and the long arm of chromosome 19 (1p/19q co-deletion) is almost an exclusive feature of tumors with an Oligodendroglial component. The presence of this molecular marker has been correlated with good response to chemotherapy and radiation therapy and improved prognosis in patients. A possible theory is that arms of these chromosomes may encode for proteins providing resistance to chemo- and radiation therapy. The presence of this co-deletion is also associated with mutation in IDH-1, which as mentioned above, gives a better prognosis. This co-deletion is also seen in low-grade gliomas which express proneural genes (proneural gliomas) which are linked with superior overall survival and progression-free survival in this subset of patients.

3. Methylguanine Methyltransferase (MGMT) is a DNA repair enzyme which reverses the effect of the alkylating agent, temozolomide. Temozolomide is an oral chemotherapy drug approved the FDA in the US in 2005 for treatment of adult patients with newly diagnosed Glioblastoma along with radiation therapy after its use in a clinical trial has shown significant improvement in survival. It acts by methylating the O6 position of the nucleotide guanine found in the DNA strand, thus, enabling tumor DNA breakage leading to cell death. MGMT counteracts this by transferring the methyl group unto itself. Methylation or ‘silencing’ of the MGMT gene promoter causes less expression of the MGMT protein. This ‘turns off’ production of this protein, consequently, making the tumor more responsive to temozolomide and prolonging patient survival. Hence, the presence of MGMT methylation status provides improved temozolomide response and improved survival in glioma patients.

4. BRAF gene mutations have been associated with development of a variety of cancers like melanoma, lymphoma, colorectal cancer, papillary thyroid cancer, nonsmall cell lung cancer and brain tumors like glioblastoma and pilocytic astrocytomas. The BRAF gene encodes the BRaf protein which is important in cell signalling for directing growth. This is highly expressed in neuronal tissues, melanocytes and hematopoietic cells.  The presence of BRAF V600E mutation is found in pilocytic astrocytoma, ganglioglioma, pleomorphic xanthoastrocytomas and pediatric diffusely infiltrating gliomas  and in less than 2% of comparable adult gliomas. Identification of BRAF gene mutation can help diagnose and differentiate a brain tumor from other entities such as reactive gliosis or scarring. Recent trials are focusing on creating agents to target the cellular signalling pathways where the BRAF gene is involved. At present, these BRAF inhibitors are active and well-tolerated for these patients; however, the evidence is still anecdotal and prospective clinical studies are yet to be conducted and concluded.

It is exciting that these molecular markers are made available to Filipinos by St. Luke’s Medical Center. The St. Luke’s Comprehensive Brain Tumor Service has been using these molecular markers to treat Filipino patients with outcomes comparable to other Neuro-Oncology centers abroad. Every Filipino with a brain tumor should be “fingerprinted”.

Dr. Roy Allan Dominique G. Torcuator is the Head of the Comprehensive Brain Tumor Service of St. Luke’s Medical Center-Quezon City and Global City. He earned his degree in medicine from the University of the East - Ramon Magsaysay Memorial Medical Center and completed clinical fellowship training in Image Guided Neurosurgery at Brigham and Womens Hospital-Harvard Medical School, Boston, MA; Clinical Neuro-Oncology at Henry Ford Hospital in Detroit, Michigan; and University of Toronto - Toronto Western Hospital, Canada. Formerly, he was senior staff neuro-oncologist at the Hermelin Brain Tumor Center at the Henry Ford Health System, Detroit, Michigan. He is a Diplomate of the Philippine Board of Neurological Surgery and a Fellow of the  Academy of Filipino Neurosurgeons.