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International Team Reports on Genomic Analyses of Pediatric Brain Cancer

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – Childhood brain tumors from individuals with a type of cancer called medulloblastoma contain a fraction of the genetic mutations found in adults with the disease, according to a genomic study appearing online today in Science.

Researchers from the US, Brazil, and Canada used a combination of whole exome sequencing and microarray analyses to identify mutations and copy number changes in nearly two dozen pediatric brain tumors. As in adult forms of the disease, they found that a sub-set of these tumors contain mutations in Hedgehog or Wnt signaling pathways.

But they also found additional mutations in the childhood cancer that alter pathways mediating epigenetic processes. And these tumors contained between five and 10 times fewer mutations overall than those found in adult medulloblastomas.

"These analyses clearly show that genetic changes in pediatric cancers are remarkably different from adult tumors," co-senior author Victor Velculescu, an oncology researcher at the Johns Hopkins Kimmel Cancer Center, said in a statement. "With fewer alterations, the hope is that it may be easier to use the information to develop new therapies for them."

Medulloblastoma — a cancer that springs up in the cerebellum and often travels to other parts of the central nervous system — affects about one in every 200,000 children under 15 years old, the researchers noted, frequently leading to death or long-term disability in those affected.

Although past research on adult medulloblastoma has led to the identification of at least two forms of medulloblastoma — one involving Wnt signaling pathway mutations and another changes to the Hedgehog signaling pathway — there is still much to be learned about the complete set of genetic changes contributing to the disease, they added.

And because relatively little was known about the genetics of childhood medulloblastoma, the researchers decided to apply genomic approaches to explore the pediatric form of the disease.

To do this, the team used the Sanger approach to sequence protein- and microRNA-coding regions of 22 pediatric medulloblastoma genomes, along with a healthy control sample. They also evaluated copy number patterns in the tumors using high-density Illumina arrays containing around one million probes.

When they did find mutations that appeared to be tumor specific, they then re-sequenced suspicious bits of the genome in tumor and matched normal samples from affected individuals using either Sanger or Illumina Genome Analyzer II sequencing.

Overall, the team identified 11 mutations per tumor, on average. Nearly 90 percent of the 225 total mutations detected represented point mutations, they added. And almost three-quarters of these point mutations appear to be non-synonymous changes.

Their copy number analyses, meanwhile, turned up 78 focal amplifications and 125 homozygous deletions in tumor samples.

By evaluating another 66 pediatric and adult medulloblastoma tumor samples, the researchers started unraveling the prevalence and consequences of mutations found in tumors from at least two individuals.

Together, their findings indicate that each pediatric brain tumor carried an average of around eight non-silent mutations — some five to 10 times fewer than the number of genetic changes detected in adult tumors in past studies.

These mutations affected some of the same genes and pathways implicated in adult medulloblastoma studies, they noted. For instance, 17 percent of childhood tumors contained mutations affecting the PTCH1 gene in the Hedgehog pathway and 13 percent carried mutations to the Wnt pathway gene CTNNB1.

But the team also uncovered mutations in genes not previously linked to medulloblastoma. Among them: the histone-lysine N-methyltransferase coding genes MLL2 and MLL3.

Some 20 percent of the medulloblastoma tumors tested contained mutations affecting MLL2, MLL3, or other genes in the same pathway, the researchers reported, suggesting alterations to epigenetic pathways — including those involved in brain development — may be particularly pertinent to childhood forms of the brain cancer.

"These results demonstrate key differences between the genetic landscapes of adult and childhood cancers, highlight dysregulation of developmental pathways as an important mechanism underlying [medulloblastomas], and identify a role for a specific type of histone methylation in human tumorigenesis," they wrote.

"We now know what many pieces of the medulloblastoma puzzle are," co-senior author Bert Vogelstein, co-director of Johns Hopkins' Ludwig Center, said in a statement. "Now, we must figure out how to put the puzzle together and zero in on parts of the puzzle to develop new therapies."