Researchers have identified six germline mutations that explain 6% of medulloblastoma cases; the mutations were associated with four consensus subgroups of the disease. Their results could inform future genetic testing, treatment, and surveillance of patients with medulloblastoma.

A recent study has revealed new details about the genetic underpinnings of medulloblastoma: Scientists identified six germline mutations responsible for 6% of medulloblastoma cases and matched them to previously established disease subtypes, research that could inform genetic testing, treatment, and surveillance of patients for a second cancer.

Over the past decade, “we've used a variety of different large-scale sequencing approaches to try to understand the molecular basis of the disease,” says lead author Paul Northcott, PhD, of St. Jude Children's Research Hospital in Memphis, TN. For example, previous studies have established consensus medulloblastoma subgroups—WNT, SHH, Group3, and Group4—that differ in demographics, genetic makeup, and clinical outcomes. However, these efforts have focused on changes in the tumor genome. “Our main goal was to look for [mutations] that were present in the germline of these patients that could be predisposing to medulloblastoma development.”

Northcott's team analyzed whole-genome and whole-exome sequences from germline and tumor samples from 1,022 patients with medulloblastoma in retrospective and prospective studies. They compared these sequences with sequences from 53,105 healthy controls, restricting the analysis to 110 known cancer predisposition genes. They found that pathogenic alterations in six genes—APC, BRCA2, PALB2, PTCH1, SUFU, and TP53—accounted for 6% of medulloblastoma cases.

When they categorized patients by medulloblastoma subgroup, they determined that certain mutations are more common in certain subgroups, and for patients of certain ages. For example, 15% to 20% of patients in the SHH subgroup had a mutation in one of the six genes. SUFU and PTCH1 mutations occurred in infants in the SHH subgroup, whereas TP53 mutations were present in children in the SHH subgroup. Patients with APC mutations fell into the WNT subgroup, and PALB2 and BRCA2 alterations occurred across the other three subgroups.

“It's not necessarily that we've uncovered new genes, but what we've done now is confirmed their overall rate of pathogenic germline variation, and most importantly, we've confirmed their subgroup specificity and their age-related associations in a massive cohort,” Northcott says.

Because mutations in these six genes can be associated with increased risk of other cancers or resistance to treatment, all patients with medulloblastoma should undergo genetic testing based on disease subgroup. “Clinical signs or patchy family histories are insufficient to really establish who should be tested and who should be watched and potentially altered in terms of course of treatment,” Northcott says.

“I call it the yin and yang of cancer genetics,” says Uri Tabori, MD, of The Hospital for Sick Children in Toronto, ON, who was not involved in the study. “There is the impact of the genetics of the cancer on the germline, and the impact of the germline on how to manage the cancer. For years now, we sequenced the tumors, but we never looked at the germline.”

He adds that the study shows “we can use the tumor analysis to predict which patients will have a germline predisposition, and we can use the germline mutations to predict how the tumor will behave.”

Roger Packer, MD, of Children's National in Washington, DC, who was also not involved in the research, hopes future studies will investigate how to improve treatment of patients with germline mutations, and move beyond the 110 known cancer predisposition genes.

“How many other cancer predispositions are leading towards development of these tumors? Is it another 5%? Is it another 2%? Is it none of them? We don't know,” he says. “We're still scratching the surface of what other predispositions may be present.” –Catherine Caruso