An extensive genomic study of the childhood cancer neuroblastoma reinforces the challenges in treating the most aggressive forms of this disease. Contrary to expectations, the scientists found relatively few recurrent gene mutations—mutations that would suggest new targets for neuroblastoma treatment. Instead, say the researchers, they have now refocused on how neuroblastoma tumors evolve in response to medicine and other factors.
"This research underscores the fact that tumor cells often change rapidly over time, so more effective treatments for this aggressive cancer will need to account for the dynamic nature of neuroblastoma," said study leader John M. Maris, M.D., director of the Center for Childhood Cancer Research at The Children's Hospital of Philadelphia (CHOP).
Striking the peripheral nervous system, neuroblastoma usually appears as a solid tumor in a young child's chest or abdomen. It comprises 7 percent of all childhood cancers, but causes 10 to 15 percent of all childhood cancer-related deaths. Neuroblastoma is notoriously complex, with a broad number of gene changes that can give rise to the disease.
Maris headed the multicenter research collaborative, the TARGET (Therapeutically Applicable Research to Generate Effective Treatments) initiative, which released its findings today in Nature Genetics. This largest-ever study genomic study of a childhood cancer analyzed DNA from 240 children with high-risk neuroblastomas. Using a combination of whole-exome, whole-genome and transcriptome sequencing, the study compared DNA from tumors with DNA in normal cells from the same patients.
Researchers at CHOP and other centers previously discovered neuroblastoma-causing mutations, such as those in the ALK gene. In the subset of patients carrying this mutation, oncologists can provide effective treatments tailored to their genetic profile.
"A few years ago, we thought we would be able to sequence the genomes of individual patients with neuroblastoma, detect their specific cancer-causing mutations, and then select from a menu of treatments," said Maris. The oncology researchers designed the TARGET study to perform genomic analyses of a large cohort of high-risk neuroblastoma patients, with the goal of mapping out a limited number of treatment strategies. This approach would represent a significant step forward in personalizing neuroblastoma therapy.
However, while the researchers confirmed that roughly 10 percent of the study's neuroblastoma patients had ALK mutations, and found that a handful of other gene mutations each accounted for percentages in the single digits, there were relatively few recurrent mutations in somatic (non-germline) cells. "The relative paucity of recurrent mutations challenges the concept that druggable targets can be defined in each patient by DNA sequencing alone," wrote the authors.
In the absence of frequently altered oncogenes that drive high-risk neuroblastomas, the authors concluded that most such cases may result from other changes: rare germline mutations, copy number variations and epigenetic modifications during tumor evolution.
"Personalized medicine is more complex than we had hoped," said Maris. "While there are successes such as those in treating patients whose tumors harbor ALK mutations, this study implies that we must think very differently about how we'll use genomics to define treatment." Maris added that neuroblastoma researchers may need to turn to functional genomics, learning which tumors will or won't respond to treatments, as well as going beyond a static picture of a cancer cell with fixed genetic contents, to devising interventions to deal with dynamic tumor cells that evolve during nervous system development.
"The genetic landscape of high-risk neuroblastoma," Nature Genetics Advance online publication, Jan. 20, 2013.
Children's Hospital of Philadelphia: http://www.chop.edu
This press release was posted to serve as a topic for discussion. Please comment below. We try our best to only post press releases that are associated with peer reviewed scientific literature. Critical discussions of the research are appreciated. If you need help finding a link to the original article, please contact us on twitter or via e-mail.
From Dr Strangelove and water fluoridisation to climate change, scientific method and facts are not always enough to win over the sceptics
On a blog post at PLOS, the tropical disease expert Peter Hotez and postdoctoral fellow Jennifer Herricks take a run through the data on the biggest killers of children around the world in 2013, part of a new dataset from Global Burden of Disease study published in the January Lancet.
Tory MP David Tredinnick seems to believe that astrology could inform and improve UK healthcare. This view is misguided and potentially dangerous
Resistance to vital antimalarial drugs called artemisinins has spread across Burma to the Indian border. If not contained, it could ultimately hit Africa hard
Clostridium difficile sickens nearly half a million Americans annually, killing about 29,000, say federal health officials. They warn hospitals and nursing homes to tighten hygiene protocols.
Study looking at transmission among men who have sex with men recruited 545 participants at high risk of contracting HIV A daily pill can effectively protect gay men against infection with HIV
An experimental therapeutic vaccine from Danish drugmaker Bavarian Nordic helped significantly extend survival in patients with advanced prostate cancer, according to results of a small early-stage trial conducted by the U.S. National Cancer Institute.
Scientists interviewed more than 1,000 men, women and children who were forced into sex work and hard labor. The result is the largest study to detail the health of human trafficking survivors.
Gerbils from Asia rather than black rats were responsible for repeated outbreaks of the bubonic plague in Europe, a study suggests.
The so-called "cuddle-chemical" seems to block the action of alcohol in the brain, preventing the tell-tale signs of drunkenness in rats