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Studies Improve Characterization of Childhood Brain Cancer Subtypes

NEW YORK (GenomeWeb News) – Three genomic studies published in Nature this week are expanding understanding of the mutations and structural variations that define the four subtypes of medulloblastoma, a childhood brain cancer.

"We tend to treat all medulloblastomas as one disease without taking into account how heterogeneous the tumors are at the molecular level," Yoon-Jae Cho, a neurology researcher affiliated with Stanford University, the Broad Institute, Harvard Medical School, and Children's Hospital Boston, said in a statement.

Cho was co-senior author on a study appearing online in Nature this past weekend, in which he and colleagues the US, Canada, and Germany did exome sequencing on primary tumor and matched normal samples from 92 individuals with medulloblastoma.

Analyses of the exomes — each sequenced to a depth of 106-fold, on average — uncovered a median of 16 somatic mutations per tumor. Not surprisingly, the mutation and copy number profiles varied across the molecularly defined medulloblastoma subtypes, known as WNT, SHH, Group 3, and Group 4.

And while many of the alterations were restricted to just one or a few tumors, the team tracked down a dozen genes that they defined as frequently mutated.

Consistent with findings published earlier this month by Pediatric Cancer Genome Project researchers, many of the medulloblastoma-related mutations turned up in genes believed to govern epigenetic processes. In particular, half of the recurrently mutated genes fell in histone modification and/or chromatin remodeling-related pathways.

Also over-represented among the mutated genes were those coding for nuclear co-repressor complex members and proteins involved in hedgehog and WNT/beta-catenin signaling pathways.

For example, the DDX3X gene, which codes for an RNA helicase enzyme, was often mutated in tumors that also carried mutations to beta-catenin gene CTNNB1, researchers reported. Their follow-up experiments also hinted that such combinations could lead to enhanced signaling via the WNT/beta-catenin pathway.

Together, such results offer "a finer-grained view of the genetic landscape of these tumors and provides us with some leads on how to develop new therapies," according to Cho, who co-chairs a Pediatric Brain Tumor Consortium committee focused on finding promising candidates for future clinical trials.

"Our plan is that within the next one to two years we will be able to offer kids a new set of compounds that have a clear biological rationale based on our genomic studies," he said in a statement.

Along with Sunday's study, Cho co-authored two other medulloblastoma studies out today in Nature.

In the first of these, researchers based in Germany and elsewhere who are involved in the International Cancer Genome Consortium's PedBrain Tumor Project did genomic analyses on 125 individuals with medulloblastoma who were between the ages of 0 and 17 years old as part of an effort to characterize mutational profiles in the medulloblastoma subtypes.

That study involved whole-genome sequencing of 39 tumor-normal pairs and exome sequencing on tumor and normal samples from 21 individuals.

Based on the mutations that popped out of tumor sequences in the genome and exome discovery set, the investigators focused on 2,734 suspicious genes for targeted sequencing in another 65 medulloblastoma tumors. They also used RNA sequencing to track down new fusion genes in some of the brain cancers.

In addition to finding new and known medulloblastoma genes, including several genes coding for chromatin-modifying proteins, that group saw a jump in tumor mutation rate with advancing medulloblastoma patient age. It also found some genes and patterns similar to those described in the accompanying Nature studies, uncovering just eight recurrently altered genes that contained somatic mutations in 3 percent of the tumor samples or more.

And again, researchers were keen to start teasing apart subtype specific features in the tumors, particularly those belonging to Group 3 and Group 4 subtypes, which generally have the worst outcomes.

"This large, integrative genomics study has provided a detailed insight into new mechanisms contributing to medulloblastoma tumorigenesis and disclosed novel targets for therapeutic approaches, especially for Group 3 and 4 patients," authors of that study concluded. "The molecular subgroup-related enrichment of many alterations highlights the importance of considering this distinguishing factor in research, trial design, and clinical practice."

For their part, members of the Medulloblastoma Advanced Genomics International Consortium, or MAGIC, used Affymetrix arrays to find somatic copy number changes in each of the medulloblastoma subtypes.

As they reported today, MAGIC investigators assessed almost 1,100 medulloblastomas, unearthing an abundance of copy number alterations. The genes affected by these copy number shifts differed from one subtype to the next, again pointing to possible treatment targets.

In the Group 3 tumors, for example, they saw recurrent copy number changes involving components of the TGF-beta signaling pathway. Group 4 tumors, on the other hand, were prone to somatic copy number alterations affecting the NF-kappa B signaling pathway.

"We identify a number of highly targetable, recurrent, subgroup-specific [somatic copy number alterations] that could form the basis for future clinical trials," co-corresponding authors Michael Taylor, with the Hospital for Sick Children and the University of Toronto, and Marco Mara, a University of British Columbia researcher and director of the BC Cancer Agency’s Michael Smith Genome Sciences Centre, and their colleagues wrote.

"The cooperative, global approach of the MAGIC consortium has allowed us to overcome the barrier of inter-tumoral heterogeneity in an uncommon pediatric tumor, and to identify the relevant and targetable [somatic copy number alterations] for the affected children," they added.