When it comes to brain tumors, no two are exactly the same. Even when patients receive the same diagnosis, their treatment plans and outcomes can look completely different.
“Every patient is unique and will require a specific treatment plan for their tumor,” shares Dr. Najla Kfoury-Beaumont, neuro-oncology scientist at the University of California, San Diego. “Two people may both have high-grade gliomas, but one might live for 15 months and another for three years. That difference often comes down to the tumor’s genetic makeup.”
Every brain tumor has its own genetic “fingerprint.” Doctors learn about these fingerprints by studying the tumor’s tissue after surgery or biopsy. This testing, called molecular profiling, helps them understand what makes the tumor grow and how it might respond to certain treatments.
“Once we integrate all the imaging, pathology, and genetic information, we can personalize a treatment plan for each person,” explains Dr. Kfoury-Beaumont. “That’s the beauty of modern neuro-oncology. It’s not one-size-fits-all anymore.”
If a tumor comes back, doctors may repeat this testing to see if anything has changed. That information can open new doors for treatment or clinical trial options.
Common Genetic Markers and What They Mean
IDH1 and IDH2
IDH mutations occur in more than 70 % of grade II/III gliomas. These mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes lead to the accumulation of the pro-oncogenic metabolite D-2-hydroxyglutarate and occur early in gliomagenesis. It has also been shown that IDH mutation is associated with global DNA hypermethylation and histone methylation, which could explain the slow-growing characteristic of IDH-mut gliomas and the more favorable prognosis for patients with IDH-mut gliomas.
1p/19q Codeletion
1p/19q deletion or co-deletion is the loss of both the short (p) arm of chromosome 1 and the long arm (q) of chromosome 19 and is commonly found with IDH mutations. This genetic alteration is key feature of oligodendriomas and patients with this co-deletion have a favorable prognosis and a better response to treatment due to the loss of mediators of resistance to therapy.
This co-deletion is linked to increased sensitivity to chemotherapy and radiation. It has been shown that the loss of specific genes located on these arms are involved in conferring resistance to treatment and the loss of these genes, makes the tumor less resilient.
MGMT
MGMT (O6-methylguanine-DNA methyltransferase) gene encodes a DNA repair protein and is shown to be silenced through promoter methylation in gliomas. When MGMT is not methylated and is active, it produces an enzyme that removes alkyl groups from DNA (O6-guanine).
Chemotherapy treatment with temozolomide (TMZ) works by damaging the DNA of rapidly dividing cancer cells by attaching a specific molecule to guanine. Therefore, when MGMT is unmethylated and active, it removes this molecule and interferes with the TMZ effectiveness. Patients with hypermethylated MGMT tumors have a better response to TMZ and hence better survival rates.
EGFR
EGFR (epidermal growth factor receptor) is the most frequently altered gene in glioblastoma (60% of patients). EGFR alterations include gene amplification, mutation, rearrangement, and splicing site changes, with the most frequent being EGFR amplification. These alterations lead to aberrant EGFR signaling pathways that contribute to promoting tumor cell proliferation and survival, as well as establishing an immunosuppressive tumor microenvironment that allows for tumor immune escape.
Understanding a tumor’s genetic makeup not only guides treatment, it can also connect patients to clinical trials designed specifically for their type of mutation.
“The molecular profile of a tumor is key to developing personalized therapy,” says Dr. Kfoury-Beaumont. “It helps us match patients with the most promising clinical trials and treatment strategies available.”
At large academic centers like UC San Diego, patients benefit from a multidisciplinary team of neurosurgeons, neuro-oncologists, and radiation oncologists. All working together to create a treatment plan that fits the person, not just the diagnosis.
When asked what gives her the most optimism about the future of brain tumor research, Dr. Kfoury-Beaumont doesn’t hesitate: “Vorasidenib is the most exciting drug discovery right now. I’m hopeful that we’ll soon see more targeted treatments for other tumor types as well, especially those without IDH mutations.”
She believes meaningful change is coming soon. “It may take a few more years, but I’m confident that within this decade, we’ll see more personalized therapies becoming part of everyday care.”
Every brain tumor tells its own story through its genes, and understanding that story gives doctors the power to deliver care that’s more personal, more effective, and more hopeful. As Dr. Kfoury-Beaumont reminds us, “The more we learn about these molecular differences, the closer we get to truly individualized treatments that give each patient their best chance.”
Question to ask your doctor
- What is the IDH status of the tumor?
- Will tumor tissue undergo next-generation whole genome sequencing and chromosome analysis for copy number variation?
- What is the tumor case volume in your neurosurgeon practice? (it is important to make sure your neurosurgeon has expertise in your tumor type and has performed a good number of cases for that tumor type)
- Will the patient’s care team include a multidisciplinary team consisting of a neurosurgeon, neuro-oncologist and specialized radiation oncologist?
- Follow up to #4-Will my tumor case be presented at the tumor board for a discussion by the whole care team?