Cancer Linked to Missing DNA

June 17, 2009 -- Scientists reported Wednesday the first link ever found between cancer and a type of genetic defect, called copy number variation, characterized by missing or extra bits of DNA.

The breakthrough came in a study on neuroblastoma, a devastating pediatric disease of the nervous system that accounts for 15 percent of all cancer deaths among young children.

Researchers led by John Maris of Children's Hospital of Philadelphia discovered that a copy number variation (CNV) on chromosome 1 can play a key role in the development of the disease, which strikes most commonly in infancy and is often fatal.

The absent stretch of DNA occurs within a group of genes involved in the development of the nervous system, and affects how much one of these genes is manufactured within both normal and the cancerous cells.

"This is a brand new area -- we never suspected that this family of genes played a role in neuroblastoma," Maris said in an phone interview.

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In research published last year, Maris and others isolated another gene, known as ALK, that can by itself give rise to a rare hereditary form of the disease.

Last month, they unveiled common variants in a third gene, BARD1, that also enhances a child's susceptibility, though less dramatically.

The new research, published in the British journal Nature, is significant not only because it adds yet another piece to the neuroblastoma puzzle, but also because it implicates a whole new category of genetic material as potential cancer agents.

It has been widely suspected that CNVs could lead to cancerous tumors, but evidence had remained elusive.

Using powerful computers, Maris compared long stretches of DNA in cancer patients and healthy persons to conduct what is called a genome-wide association study.

The technique has, over the last decade, uncovered hundreds of links between disease and DNA, but was designed to hunt for a different kind of genetic glitch, not copy variation.

"The achievement here was proving the hypothesis that CNVs do, indeed, predispose to this paediatric cancer," Maris said in a phone interview.

"We can infer that it's not just going to be true for neuroblastoma. My expectation is that there will be many reports following on this of similar types of associations in other cancers," he said.

The study also highlights the fact that, when it comes to disease, including cancer, there is no hard-and-fast definition of what is hereditary.

Only a handful of conditions -- the so-called Mendelian diseases, such as muscular dystrophy and cystic fibrosis -- are caused by mutations in a single gene.

Most are triggered by a complex web of genetic and environmental factors that are difficult to tease apart.

"Like all human cancers, a small percentage of neuroblastoma runs in families -- usually one or two percent -- and the rest seemingly occur by chance," explained Maris.

"The genome-wide association field is showing that it is not chance. There actually is a genetic susceptibility, but it takes a perfect storm of inheriting the right mix of these risk factors from Mom and Dad."

With some variation worldwide, approximately 100 in a million children under 15 develop neuroblastoma. Incidence decreases with age, and is up to 10 times higher among infants than young teenagers.

Related Links:

The Journal Nature

NIH: Neuroblastoma

HowStuffWorks.com: DNA