The company believes that this is not only the most comprehensive genomic analysis of neuroblastoma published to date, but also the largest whole-genome survey of a single cancer type formally reported in the literature. Researchers in the Netherlands compared the DNA from 87 tumor-normal pairs (174 human genomes) derived from untreated neuroblastoma patients with tumors at different clinical stages. The genomes were sequenced using Complete Genomics’ genome sequencing platform to an average of 50x coverage, and the data were analyzed using the company’s local de novo assembly pipeline and Complete Genomics Analysis Tools (CGA™ Tools) software. This research was funded by the parent organization Villa Joep and childhood cancer foundation KiKa.
Neuroblastoma is diagnosed in approximately 1 in 100,000 children, typically when younger than five years of age, and develops in nerve tissue in the adrenal gland, neck, chest, or spinal cord, according to the National Institutes of Health. The mechanism by which this disease progresses has been poorly understood — while some patients have good survivability, the prognosis for late-stage patients is often poor. Unusually, some metastatic neuroblastomas undergo spontaneous regression, a phenomenon which could suggest new diagnostics or therapies.
“In conjunction with our excellent sample collection and the efforts of our own bioinformatics team, Complete Genomics’ service has allowed us to publish one of the leading scientific articles in this field,” said Prof. Dr. Rogier Versteeg, head of the department of Oncogenomics of the Academic Medical Center, University of Amsterdam. “Interestingly, these results could only have been obtained with whole genome sequencing technology. Many of these events would have been missed by targeted exome or lower-depth genome sequencing approaches.”
Overall the authors observed a relatively low rate of somatic single nucleotide variants in these cancers and few candidate causal protein-altering point mutations, consistent with other published work on childhood tumors.
In contrast, a substantial number of somatic copy number and structural variations (SVs) were found that appeared to affect genes, suggesting these mutations may play an important role in the cancer’s development. SVs were seen repeatedly across the patients in genes known to regulate nerve cell growth and cell structure, for example.
“Our customers continue to advance medical knowledge of potentially fatal conditions such as neuroblastoma that need to be understood better at the genetic level,” said Dr. Clifford Reid, chairman, president and CEO of Complete Genomics. “We can only hope the targets and molecular mechanisms highlighted by this study will spur the development of diagnostics and treatment options for neuroblastoma patients.”
Furthermore, in 18 percent of the patients the authors observed a systematic “shredding” of the tumor chromosomes, a phenomenon known as chromothripsis. These particular tumors were associated with poor outcomes. Mutations observed in the study suggest molecular mechanisms which may mediate these chromothripsis events, a finding that could have implications for neuroblastoma as well as other cancers exhibiting chromothripsis.
"The investigators chose more than 1,000 candidate somatic mutations for independent validation from the Complete Genomics results, and they confirmed the great majority of those events," said Stephen Lincoln, vice president of scientific applications at Complete Genomics. "High sensitivity and specificity were achieved in spite of the challenging nature of neuroblastoma genomes, namely the pronounced degree of structural variation and the relatively low somatic point mutation rate."