Targeted therapies — treatments designed around specific molecular features of a tumor — are changing the way some brain tumors are diagnosed and treated. But identifying those features requires looking beyond what a tumor looks like on an MRI or under a microscope.

Next-generation sequencing (NGS) allows physicians to analyze many genes within a tumor at the same time, identifying molecular changes that can help define exactly what type of tumor a patient has and, increasingly, how it may be treated.

For patients with brain tumors, this molecular information has become an important part of precision medicine: combining imaging, pathology and genetic findings to develop a more complete diagnosis and a more individualized treatment plan.

NGS in a Nutshell

John Paul Bouffard, MD, a neuropathologist who works closely with Atlantic Brain & Spine neurosurgeons in the diagnosis of brain tumors, offers a simple way to understand next-generation sequencing: think about your DNA like a library.

That library contains thousands of genes — an enormous amount of biological information. Rather than looking for one genetic change at a time, NGS can analyze many genes simultaneously and identify mutations and other molecular alterations within a tumor.

For brain tumors, those findings can provide information that cannot always be determined from imaging or traditional pathology alone. Depending on the tumor, testing may look for changes involving genes or molecular markers such as IDH1/IDH2, 1p/19q, MGMT, BRAF, H3 and others.

Not every molecular finding changes treatment. But some help establish the diagnosis, some provide information about how a tumor may behave, and others may reveal a treatment or clinical trial specifically matched to that tumor.

Diagnoses Driven by Molecular Science

Brain tumor diagnosis has changed significantly in recent years. Traditionally, pathologists classified tumors primarily by examining tumor cells under a microscope. Today, many brain tumors are defined using an integrated diagnosis that combines what the tumor looks like with its molecular characteristics.

This is particularly important for gliomas.

For example, tumors that may look similar under a microscope can represent biologically different diseases depending on their molecular profile. In adult diffuse gliomas, testing for an IDH mutation is a critical first distinction. Additional findings, such as deletion of chromosomes 1p and 19q, help distinguish oligodendroglioma from astrocytoma.

Modern classification also changed the definition of glioblastoma. Glioblastoma is now classified as an IDH-wildtype tumor. A diffuse astrocytic tumor with an IDH mutation is instead classified as astrocytoma, IDH-mutant, which may be assigned Grade 2, 3 or 4 depending on its features.

Other molecular markers can provide different kinds of information. MGMT promoter methylation, for example, can help predict how likely a glioblastoma is to respond to the chemotherapy drug temozolomide.

Together, these findings allow the treatment team to move beyond simply asking “What does this tumor look like?” toward the more important question: “What tumor does this patient actually have?”

Targeted Brain Tumor Treatments

One of the most important advances in molecular testing is that identifying a tumor’s genetic alterations can sometimes do more than establish the diagnosis — it can reveal a specific treatment opportunity.

A major example involves mutations in the IDH1 and IDH2 genes, which occur in many lower-grade diffuse gliomas. In 2024, the FDA approved vorasidenib (Voranigo®), an oral IDH1/IDH2 inhibitor, for adults and children age 12 and older with certain Grade 2 IDH-mutant astrocytomas or oligodendrogliomas following surgery. The treatment directly targets the molecular alteration driving these tumors.

Molecularly guided treatment is also expanding into other types of glioma. In 2025, the FDA granted accelerated approval to dordaviprone (Modeyso®) for adults and children age 1 and older with progressive diffuse midline glioma carrying an H3 K27M mutation after prior therapy — the first FDA-approved systemic treatment specifically for this molecularly defined disease.

These therapies do not apply to every patient with a brain tumor. But they illustrate why molecular testing has become increasingly important: a mutation that once provided primarily diagnostic or prognostic information may now identify an FDA-approved treatment or eligibility for a clinical trial.

For patients whose tumors do not have an established targeted therapy, NGS may still identify molecular alterations being studied in clinical trials. This allows the multidisciplinary treatment team to consider investigational options based on the biology of the individual tumor rather than diagnosis alone.