Medulloblastoma is the most common malignant brain tumor found in children, typically arising in the cerebellum, the area responsible for coordination and balance. This fast-growing, high-grade tumor can spread throughout the central nervous system via the fluid that surrounds the brain and spinal cord. For many years, medulloblastoma was treated as a single disease. However, recent scientific advancements have revealed that it is actually a heterogeneous collection of distinct diseases, leading to a paradigm shift toward a more precise classification system.
Why Molecular Subtyping is Essential
Historically, medulloblastoma classification relied on histology, categorizing tumors based on their appearance under a microscope (e.g., classic, desmoplastic/nodular, or large cell/anaplastic variants). This traditional method proved inadequate because tumors that looked identical often behaved radically differently, showing varied responses to treatment and different outcomes. Modern molecular classification addressed this limitation by determining the tumor’s true biological identity beyond its physical appearance.
Molecular subtyping involves analyzing the tumor’s genetic material (DNA and RNA) to identify unique genetic drivers and gene expression patterns. This process identifies the specific mutations or activated signaling pathways that caused the cancer. All medulloblastoma tumors fall into one of four consensus molecular subgroups, each driven by a distinct biological mechanism. This molecular profile is now recognized as the most accurate predictor of a patient’s prognosis and treatment response.
The Four Distinct Medulloblastoma Subgroups
WNT-Activated Subgroup
The WNT-activated subgroup is the least common, accounting for approximately 10% of all medulloblastoma cases. These tumors are named for the activation of the WNT (Wingless/Integrated) signaling pathway, often due to mutations in the CTNNB1 gene. WNT-activated medulloblastoma is typically seen in older children, adolescents, and adults, generally arising near the cerebellar peduncle. This subgroup has the most favorable prognosis, with a five-year survival rate exceeding 90%.
SHH-Activated Subgroup
The Sonic Hedgehog (SHH)-activated subgroup represents about 25% to 30% of all medulloblastomas. This group has a bimodal age distribution, predominantly affecting infants and adults. Tumorigenesis is driven by uncontrolled activation of the SHH signaling pathway, which is normally responsible for development. Genetic drivers frequently include loss-of-function mutations in PTCH1 or SUFU, or activating mutations in SMO. The SHH subgroup is further refined by the presence or absence of a TP53 mutation, as TP53-mutant tumors carry a significantly worse prognosis.
Group 3
Group 3 medulloblastoma accounts for approximately 25% of cases and is associated with the poorest clinical outcome. These tumors primarily affect infants and young children and are more common in males. The most significant molecular feature is the frequent amplification of the MYC oncogene, which drives aggressive tumor growth and is strongly linked to a high risk of metastasis. Up to 40% of Group 3 tumors have already spread to the central nervous system at the time of diagnosis. The underlying signaling pathways driving this subgroup are not as clearly defined as those for WNT or SHH.
Group 4
Group 4 is the most common subgroup, representing about 35% of all medulloblastoma diagnoses. Like Group 3, this subgroup lacks a clearly defined activated signaling pathway and typically presents in older children. Group 4 tumors often display a specific genetic abnormality called isochromosome 17q, where the long arm of chromosome 17 is duplicated. They show a predilection for males (about a 2:1 ratio). This subgroup frequently presents with metastatic disease, found in about one-third of all cases at diagnosis.
Treatment Strategies Based on Subtype
The molecular classification has fundamentally changed treatment planning, allowing for personalized, risk-adapted therapy instead of a one-size-fits-all approach. Treatment decisions now incorporate the molecular subtype alongside clinical factors such as the patient’s age and the extent of tumor spread. The goal is to maximize survival while minimizing the long-term side effects of aggressive treatments like radiation and chemotherapy on the developing brain.
WNT Treatment
For the WNT-activated subgroup, the highly favorable prognosis allows for a reduction in therapy intensity. Clinical trials are exploring reduced doses of craniospinal radiation and less aggressive chemotherapy regimens to spare children from severe cognitive and endocrine late effects. Even if WNT tumors have spread, they retain their excellent prognosis, meaning metastasis does not automatically necessitate the most aggressive treatment.
SHH Treatment
The SHH-activated subgroup has an intermediate prognosis. Its reliance on a specific signaling cascade makes it a target for novel therapies, such as drugs that inhibit the Smoothened (SMO) protein, a key component of the SHH pathway. These inhibitors are particularly focused on patients whose tumors harbor mutations upstream of SMO. For children younger than three, radiation is often delayed, and they receive high-dose chemotherapy instead to protect their developing brains from radiation damage.
Group 3 and Group 4 Treatment
Due to their aggressive nature and high risk of metastasis, Group 3 and Group 4 medulloblastomas generally require more intensive therapies. For Group 3 tumors, especially those with MYC amplification, researchers are actively seeking new therapeutic approaches to overcome the poor outcomes. This includes investigating drugs that target the downstream effects of the MYC oncogene or compounds that enhance the immune system’s ability to fight the tumor. Treatment for both groups in younger patients may involve delaying radiation to limit neurotoxicity, often using high-dose chemotherapy protocols followed by stem cell transplant.