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Integrated Medulloblastoma Genomics Study Reveals Refined View of Tumor Subtypes

NEW YORK (GenomeWeb) – A new study is providing a refined look at the molecular subtypes that can occur in a form of childhood brain tumor called medulloblastoma.

Members of an international team led by investigators in Germany and Canada analyzed somatic mutations in nearly 500 medulloblastoma tumors, along with epigenetic patterns in tumors from nearly 1,300 individuals with the malignant pediatric brain tumor condition. The findings, published online today in Nature, led to new and known medulloblastoma classifications, including methylation-based groups falling within two previously documented subtypes.

"Our highly integrative genomic analysis of the pediatric brain tumor [medulloblastoma] has enabled the discovery of new cancer genes and actionable pathways, effectively assigning candidate drivers to most tumors across molecular sub-groups," the authors wrote.

Four medulloblastoma molecular subtypes have been described through past tumor profiling projects, the team explained, including a WNT subtype marked by Wingless pathway activation and a subtype with constitutive Sonic hedgehog pathway activation, known as the SHH subgroup. The remaining two subtypes — Group 3 and Group 4 medulloblastomas — are molecularly murkier and defined mainly from expression and/or epigenetic profiles.

"Targeted therapies for [medulloblastoma] are scarce yet desperately needed, warranting intensive investigation into the full range of genetic lesions and molecular heterogeneity that contribute to [medulloblastoma] subgroups, especially as it relates to poorly characterized Group 3 and Group 4 disease," the authors explained.

Starting with sequences from matched tumor and normal samples taken from 579 individuals with medulloblastoma prior to treatment, the researchers focused on 390 whole-genome sequences and 101 exome sequences, representing 491 cases that had sufficiently high sequence quality. They also considered array-based methylation profiles for 1,256 medulloblastoma tumors and array- or RNA sequencing-based gene expression profiles for more than 550 tumors.

The team's analysis revealed two dozen medulloblastoma mutation signatures and highlighted genes that are recurrently mutated or affected by structural rearrangements across the disease or in specific subgroups, along with a non-coding mutation hotspot in the TERT gene promoter and alterations affecting histone modifier sequences.

The data also offered a clearer look at the four main medulloblastoma subtypes, identifying key mutations, expression shifts, and/or epigenetic changes. The researchers saw MYC amplifications that were specific to the Group 3 tumors, for example, as well as structural variants that were specific to one or both of the Group 3 and 4 subgroups.

When it came to medulloblastoma methylation profiles, the team teased out eight methylation-based subtypes within the Group 3 and 4 tumors, despite broader overlap between the groups. Other telling alterations turned up, too, including KBTBD4 insertions and PRDM6 activation.

"[B]y redefining molecular substructure as we have described here, new opportunities for improved risk stratification tailored to treat individual patient subtypes according to their genotypes are likely to emerge," the authors concluded.