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At AACR, Findings from Broad-Led Effort to Sequence Neuroblastoma Exomes

By Andrea Anderson

ORLANDO, Fla. (GenomeWeb News) – By sequencing 81 tumor exomes, researchers from the Broad Institute and elsewhere have identified a wide range of genes that are each mutated at low frequency in neuroblastoma, attendees of the American Association for Cancer Research annual meeting heard yesterday.

The work is being done through the National Cancer Institute's Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative. Trevor Pugh, a member of Matthew Meyerson's Broad Institute lab, presented the work during a session on genomics and potential targeted therapies of pediatric malignancies here yesterday.

Neuroblastoma is a cancer that originates in primary neural crest cells in the sympathetic nervous system, Pugh explained. Although some forms of the disease are relatively benign and low-risk, with five-year survival rates of more than 95 percent, he added, neuroblastomas at the other end of the spectrum are extremely high-risk and aggressive, with less than half of affected children surviving for five years.

So while some genetic alternations have already been detected for neuroblastoma, researchers are keen to learn more about the genetic bases of the disease, especially high-risk versions of it, in the hopes of eventually coming up with new treatments and improving outcomes.

The 81 matched tumor-normal pair samples tested came from the Children's Oncology Group Collection and were well annotated, Pugh explained, and the team had access to clinical, histological, ploidy, and SNP data for the tumors.

Researchers used a solution hybrid capture approach and high-throughput sequencing to generate sequence covering more than 85 percent of the exons in each genome. For tumor genomes they had at least 14 times coverage, while matched normal exomes were sequenced to eight times coverage or more.

When they sorted through this exome data, the team found that neuroblastoma has one of the lowest somatic mutation rates seen yet, Pugh noted, and mutation patterns hint that environmental exposures are likely less significant contributors to neuroblastoma than they are for other cancers, such as melanoma.

Overall, researchers saw four mutation groups within the neuroblastoma tumors tested, including one group with an apparent hyper-mutation phenotype.

Although several genes harbored mutations across the set of neuroblastoma tumors, very few had recurrent mutations.

Just one gene was mutated at a frequency of seven percent, followed by another gene that was mutated in around three or four percent of cases. Another 16 genes seem to be altered in between two and five percent of the tumors tested, Pugh noted, though these findings still need to be verified.

Other mutations overlapping with those found in the Catalogue of Somatic Mutations in Cancer (COSMIC) database were also present in the tumors, but many of these genes were mutated in just one of the tumors tested.

Researchers have come up with a few potential explanations for the dearth of obvious mutations, Pugh explained.

For instance, he said, it's possible that some authentic cancer-related changes were filtered out during the analysis as a consequence of neuroblastoma tumor circulating in the blood and muddying the genetic signal found in matched normal samples. The team is also considering the possibility that germline mutations might contribute to neuroblastoma.

Those involved in the study are currently following up on these and other possibilities, Pugh said, and are working on ways to adjust their somatic mutation caller to find and account for the presence of tumor cells in normal samples.