Researchers have identified six genes that predispose carriers to develop the brain tumor medulloblastoma and have used the discovery to craft genetic counseling and screening guidelines. The study appears today in the journal The Lancet Oncology.

St. Jude Children’s Research Hospital, Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ), 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 non-accidental death in US children and adolescents. The tumor includes four main molecular subgroups with different clinical and biological 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 younger than age 16 years.

But 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, and 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. Germline variations are usually inherited and carried in cells throughout the body.

“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.

“Overall, half the patients with damaging germline variations were not identified based on their family cancer histories, which clinicians have depended on,” 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.”

Coauthor Giles Robinson, MD, an assistant member of the St. Jude Department of Oncology said: “The screenings can help patients and families understand and manage their lifetime cancer risk.”