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New Medulloblastoma Predisposition Genes Result in Proposed Screening Guidelines

NEW YORK (GenomeWeb) – An international team of researchers has assessed and defined medulloblastoma predisposition genes in order to provide evidence that could be used to create screening guidelines.

Medulloblastoma is associated with rare hereditary cancer predisposition syndromes, but screening guidelines for genetic counseling and testing of pediatric patients are not available, the researchers wrote in a paper published today in Lancet Oncology. In their multicenter study, the team analyzed whole-genome and exome sequences from blood and tumor samples of patients with medulloblastoma from the International Cancer Genome Consortium, PedBrain, Medulloblastoma Advanced Genomics International Consortium, the CEFALO series, and four prospective clinical studies. They looked for rare damaging germline mutations in cancer predisposition genes.

They also performed DNA methylation profiling to determine four consensus molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGroup3), and group 4 (MBGroup4). They predicted medulloblastoma predisposition genes on the basis of rare variant burden tests and used previously defined somatic mutational signatures to further classify medulloblastoma genomes into two groups: a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8). They further investigated chromothripsis, using previously established criteria. Progression-free survival and overall survival were then modelled for patients with a genetic predisposition to medulloblastoma.

The researchers analyzed a total of 1,022 patients with medulloblastoma from the retrospective cohorts and the four prospective studies for germline mutations in 110 cancer predisposition genes. They compared these against 53,105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to their rare variant burden analysis, and estimated that germline mutations accounted for 6 percent of medulloblastoma diagnoses in the retrospective cohorts.

"The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MBSHH subgroup (20 percent in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5 percent of medulloblastoma diagnoses, with the highest prevalence [14 percent] in the MBSHH subgroup)," the authors wrote.

They also observed that patients with germline APC mutations developed MBWNT and accounted for 71 percent of MBWNT that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MBSHH. Further, they noted that germline TP53 mutations presented only in childhood patients in the MBSHH subgroup and explained more than half of all chromothripsis events in this subgroup. They also observed germline mutations in PALB2 and BRCA2 across the MBSHH, MBGroup3, and MBGroup4 molecular subgroups. These mutations were also associated with mutational signatures typical of homologous recombination repair deficiency, the researchers said.

"In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52 percent and 5-year overall survival was 65 percent; these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes," they added.

The team concluded that genetic counseling and testing should be used as a standard of care in patients in the MBWNT and MBSHH medulloblastoma subgroups because they have the highest prevalence of damaging germline mutations in known cancer predisposition genes.

The researchers also proposed criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumor characteristics. In an associated infographic released by St. Jude Children's Research Hospital, which participated in the study, they recommend testing for APC mutations for the WNT subtype, in the absence of somatic CTNNB1 mutation. In the SHH group, they recommend testing for PTCH1, SUFU, TP53, BRCA2, and PALB2. For the GRP3 and GRP4 groups, the researchers recommend testing for BRCA2 and PALB2, if the patient has a family history of BRCA-associated cancers.