Medulloblastoma: DNA Points the Way

New awareness

New international research co-led by St. Jude, the European Molecular Biology Laboratory and German Cancer Research Center in Heidelberg, and the Hospital for Sick Children in Toronto, has transformed our understanding of the inherited risks for medulloblastoma.

Until now, scientists believed most cases of medulloblastoma occurred by chance and did not run in families. But in the largest study yet of genetic susceptibility in a pediatric brain tumor, scientists learned that inherited gene mutations often play a role in its development.

The discovery has prompted new recommendations for genetic testing and counseling of medulloblastoma patients and their families.

The massive effort, co-authored by St. Jude cancer biologist and medulloblastoma expert Paul Northcott, PhD, revealed germline variations—typically inherited and carried in cells throughout the body—in six genes that together explain 5% of cases of the malignancy.

These genes include APC, PTCH1, SUFU, TP53, BRCA2 and PALB2. Mutations in these genes can disrupt their normal function, causing cancer.

Although it is the most common malignant childhood brain tumor, medulloblastoma is diagnosed in only about 400 children in the United States each year. The cancer’s odds of appearing due to inherited genes vary depending on the disease’s four subgroups. These subgroups are named WNT, sonic hedgehog, Group 3 and Group 4.

Assigning risk

Each subgroup carries different characteristics and treatment outcomes. Northcott’s paper, published in the journal Lancet Oncology, looked for gene variations related to each subgroup.

Among the most striking findings: As many as 20% of sonic hedgehog medulloblastoma cases stem from germline mutations in five out of six of the implicated genes. This places these patients and possibly their siblings not only at a higher risk of developing medulloblastoma, but also of having other cancers later in life.

Additionally, inherited genes account for about 10% of patients with WNT medulloblastoma.

“When we break this down, we clearly see different risks according to the subgroups,” says Northcott, who works in St. Jude Developmental Neurobiology. “Somewhere between one in five and one in six sonic hedgehog medulloblastoma patients have a clear hereditary predisposition based on mutations in these six genes. That’s an important finding that has significant implications for patients’ treatment and their surveillance—as well as for their siblings and parents.”

Discoveries and more discoveries

Northcott and his colleagues published another major international study in 2017 that revealed the genomic changes responsible for more than 75% of medulloblastoma tumors. The scientists also discovered two new suspected cancer genes found only in the least-understood disease subgroups.

Combined, the pair of efforts help round out scientists’ understanding of the genes at play in this brain tumor.

“In the earlier study, we focused on the medulloblastoma tumors themselves, describing their molecular landscape and the genes that were mutated,” Northcott says. “In this case, we’ve studied the germline—the normal DNA that’s present in every cell of these patients.”

Compelling comparisons

In their most recent study, the researchers analyzed germline DNA samples from 1,022 patients with medulloblastoma and 58,000 individuals with no history of cancer.

The scientists used next-generation gene sequencing— a process that deciphers the exact makeup of a DNA molecule—to compare how often variants in 110 cancer predisposition genes occurred in the medulloblastoma patients and the healthy subjects. These methods teased out six high-risk gene variants that show up in medulloblastoma patients far more often than in healthy people.

The findings, Northcott notes, are especially compelling because the healthy comparison group was so large.

“We focused only on the strong predisposition genes, where there’s plenty of evidence that mutations in these genes are known to cause cancer,” he says.

“When we see a variant that is much more prevalent in medulloblastoma patients compared to 58,000 normal, healthy controls,” Northcott adds, “we can be pretty confident that this gene is playing a role.”

Risky business

The study spotlights an urgent need to make genetic counseling and testing the standard of care for many medulloblastoma patients, particularly those in the sonic hedgehog and WNT subgroups.

Northcott and his team have created detailed recommendations guiding clinicians on which types of other cancers to watch for in medulloblastoma patients—and in some cases, their relatives—based on genes and family history.

For example, between 5 and 10% of WNT subgroup patients have an inherited mutation in the APC gene, which is tightly linked to the development of colorectal cancer and other malignancies.

“These medulloblastoma patients might assume they’re free and clear because they’ve survived their brain cancer, but they’re certainly at risk for other cancers,” Northcott says. “They also have to be careful with the treatments they’re given for their medulloblastoma, because that could make them more prone to develop second cancers.”

Total care

Shadow’s mom, Jennifer, says she’s grateful for the St. Jude efforts to uncover the genetic underpinnings of medulloblastoma. While the family’s Native American heritage isn’t specifically linked, the mother of four has certainly wondered if her son’s case stemmed from something in their DNA.

Ever the bookworm and smitten with adventure novels and outdoor-themed magazines, Shadow has “bounced back completely” from his treatment, which he finished in October 2017 with no evidence of disease. He undergoes imaging scans every three months at St. Jude to confirm he’s still cancer free.

“It’s a complete and total mystery to us, and we would love to find out more about where this has come from,” Jennifer says. “Every bit of research is building toward finding a better way to treat this. It’s just total care, all the way around.”

From Promise, Summer 2018