Genetic Counseling and Testing for Patients With Medulloblastoma

Key Points

  • Along with APC, BRCA2, and TP53, the other predisposition genes identified in this study were PALB2, PTCH1, and SUFU.
  • The newly identified predisposition genes account for about 20% of the sonic hedgehog subgroup and about 5% of cases overall.
  • The findings led to subgroup-based counseling and screening recommendations.

Researchers have identified six genes that predispose carriers to develop medulloblastoma and have used the discovery to craft genetic counseling and screening guidelines. The study was published by Waszak et al in The Lancet OncologySt. Jude Children’s Research Hospital, Memphis; Hopp Children’s Cancer Center at the NCT Heidelberg, Germany; and The Hospital for Sick Children, Toronto, led the research.

Medulloblastoma is the most common malignant childhood brain tumor and one of the leading causes of nonaccidental death in U.S. children and adolescents. The tumor includes four main molecular subgroups with different clinical and biologic characteristics as well as treatment outcomes. Except in rare cases associated with genetic disorders like Li-Fraumeni syndrome or Gorlin syndrome, medulloblastoma was thought to occur sporadically by chance, usually in infants and children less than 16 years old.

Germline Variations

However, researchers completed apparently the largest analysis yet of genetic predisposition in a pediatric brain tumor and found that germline variations in six genes often play a role. The genes include APC, BRCA2, and TP53, which are also associated with an elevated risk for breast, colon, ovarian, and other cancers. The findings led the researchers to develop screening and counseling recommendations for patients based on the medulloblastoma molecular subgroups—WNT, sonic hedgehog, group 3, and group 4.

The newly identified predisposition genes account for about 20% of the sonic hedgehog subgroup and about 5% of cases overall.

“One in five patients with sonic hedgehog medulloblastoma had clear germline predispositions that put them and possibly their siblings at risk for developing medulloblastoma and other cancers later in life,” said Paul Northcott, PhD, an assistant member of the St. Jude Department of Developmental Neurobiology. He and Sebastian Waszak, PhD, of the European Molecular Biology Laboratory, Heidelberg, are co–first authors.

The contribution of germline variations in other medulloblastoma subgroups ranged from less than 5% in group 3 or group 4 medulloblastoma patients to about 10% of patients with WNT medulloblastoma. Overall, long-term survival is about 70% for patients with medulloblastoma but ranges widely from 95% for WNT medulloblastoma to 50% for patients with group 3 medulloblastoma.

“Overall, half the patients with damaging germline variations were not identified based on their family cancer histories, which clinicians have depended on,” Dr. Northcott said. “That highlights the urgent need to make genetic counseling and testing the standard of care for some medulloblastoma patients, particularly those in the sonic hedgehog and WNT subgroups.”

Identifying Predisposition Genes

Along with APC, BRCA2, and TP53, the other predisposition genes identified in this study were PALB2, PTCH1, and SUFU. The genetic variations are predicted to change the encoded protein and disrupt the genes’ normal function.

To find the high-risk genes, researchers compared the prevalence of rare variations in 110 known cancer predisposition genes in medulloblastoma patients from three continents to individuals without cancer. The analysis included whole-genome and whole-exome sequencing data of 1,022 patients with medulloblastoma.

The samples included tumor and normal tissue from 800 of the 1,022 patients. Investigators reported no significant difference in patients screened prospectively or retrospectively. The comparison group included exome sequencing data from more than 58,000 individuals with no cancer diagnoses.

Screening and Testing Guidelines

The findings led to the following subgroup-based counseling and screening recommendations:

WNT: Genetic counseling about possible high-risk APC germline variations should be offered to certain patients with WNT medulloblastoma. Those are patients without tumor cell (somatic) mutations in the gene CTNNB1, which codes for the protein β-catenin.

Sonic HedgehogGenetic counseling and testing should be offered to all patients in this subgroup for some or all of the following genes: SUFU, PTCH1, TP53, PALB2, and BRCA2. The analysis also revealed that high-risk germline TP53 variations were a risk factor for medulloblastoma treatment failure.

Group 3 and Group 4These subgroups account for 65% to 70% of all medulloblastoma cases, but less than 5% were associated with the cancer predisposition genes. Researchers recommend counseling and testing of PALB2 and BRCA2 in patients with family histories of breast, ovarian, or other cancers associated with mutations in BRCA genes.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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