Discovering for the first time that copy number variation or CNV, where a strip of DNA is duplicated or missing, may increase risk of developing cancer, US scientists found a link between a particular CNV and neuroblastoma, a deadly cancer that mostly affects children.
The study was led by Dr John M Maris, chief of Oncology and director of the Cancer Center at The Children’s Hospital of Philadelphia and is published in the 18 June issue of the journal Nature. Maris is also on the faculty of the University of Pennsylvania School of Medicine, and scientists from several other research centres worked on the research with him.
The discovery is particularly remarkable because it is the first to show that repeated or deleted strips of genetic code may be linked to cancer as opposed to variations in the code sequence or single nucleotide polymorphisms (SNPs or “snips”).
Using a grammatical comparison, a CNV would be a repeated or missing word in a phrase while an SNP would be one or more words spelled incorrectly.
Maris said the finding opens the door to studying how CNVs might increase cancer risk.
Neuroblastoma is the most common solid cancer of young children, sometimes beginning before birth, and accounts for 15 per cent of all early childhood deaths. It forms in the nerve tissue and usually begins in the adrenal glands that sit above the kidneys, but it can also start in the neck, chest or spinal cord. Unfortunately it has often already spread to other parts of the body before diagnosis.
Maris told the press:
“Only two years ago we had very little idea of what causes neuroblastoma.”
“Now we have unlocked a lot of the mystery of why neuroblastoma arises in some children and not in others,” he added.
Last month the team published the result of the largest gene study to date in childhood cancer research where they reported the result of a genome-wide association study that showed variants in the BARD1 gene increased a child’s susceptibility to a high-risk type of neuroblastoma.
This month they report the findings of a second genome-wide association study where using highly automated gene-analyzing technology they found a CNV along a structurally weak section of chromosome 1 that may be linked to developing neuroblastoma.
They used specimens from around the world that had been collected through the Children’s Oncology Group, and technology from the Hospital’s Center for Applied Genomics which is directed by Dr Hakon Hakonarson, a co-author on both studies.
Talking about the first study, Maris said that:
“Researchers have suspected that variants in BARD1 also increased the risk of breast cancer, but no one has found compelling evidence of this.”
But they were surprised, he added, when their genome-wide association studies “found that BARD1 is a susceptibility gene for neuroblastoma, and perhaps other cancers as well”.
He and his team are now trying to understand the underlying mechanism by which BARD1 variants affect nervous system cells to become cancerous while the child is in the womb or soon after.
Meanwhile, in the second study, with lead author Dr. Sharon Diskin, also of The Children’s Hospital of Philadelphia, Maris and colleagues found that a common CNV at a chromosome 1q21.1 is associated with the childhood cancer neuroblastoma.
That region of the chromosome contains many genes that are involved in the development of the nervous system, and the researchers found that a transcript within the inherited CNV, called NBPF23, a previously unknown neuroblastoma breakpoint family gene, is involved in the early stages of tumor formation.
These findings build on previous work by Maris and colleagues such as last year when they found the ALK gene was involved in making patients susceptible to a rare familial form of neuroblastoma. In another study they also found a region on chromosome 6 that raised the risk of a non- hereditary form of the disease.
As scientists reveal more of the genetic landscape of neuroblastoma, the better the chances of developing targeted treatments that improve the quality of life for children with this complex disease said Maris.
“Copy number variation at 1q21.1 associated with neuroblastoma.”
Sharon J. Diskin, Cuiping Hou, Joseph T. Glessner, Edward F. Attiyeh, Marci Laudenslager, Kristopher Bosse, Kristina Cole, Yaël P. Mossé, Andrew Wood, Jill E. Lynch, Katlyn Pecor, Maura Diamond, Cynthia Winter, Kai Wang, Cecilia Kim, Elizabeth A. Geiger, Patrick W. McGrady, Alexandra I. F. Blakemore, Wendy B. London, Tamim H. Shaikh, Jonathan Bradfield, Struan F. A. Grant, Hongzhe Li, Marcella Devoto, Eric R. Rappaport, Hakon Hakonarson & John M. Maris.
doi:10.1038/nature08035
Additional sources: Children’s Hospital of Philadelphia, NIH .
Written by: Catharine Paddock, PhD