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Genetic inheritance may not be key to vast majority of childhood cancers
  
By Lone Frank

Why do children get cancer? While knowledge of cancer among adults is steadily growing, the background for cancers arising in childhood has been puzzling researchers for years. Most investigators trying to tease out the causes have had their sights firmly set on genetics, but now they get a clear message from a large epidemiological study involving all Nordic countries. Look to the environment—the answer may not be only in the genes.

"What we can conclude is that less than 5 percent of all childhood cancers are heritable. For the other 95 percent there seems to be no heritable genetic contribution at all, and this now sends researchers on a hunt for environmental factors," says epidemiologist Jeanette Falck Winther of the Danish Cancer Society. She led the recent investigation of childhood cancers that builds on data from cancer registries in Sweden, Norway, Finland, and Iceland. The results drew much surprise and interest when they were recently presented at the annual meeting of the Danish Society for Cancer Research.

Ruling out inherited genes for the vast majority of childhood cancers required the analysis of 42,000 siblings of 25,000 cancer patients who had developed the disease before the age of 20. The hypothesis driving the study was that if getting cancer at a young age is somehow related to certain genes, then the risk must be greater among sisters and brothers of patients with some form of childhood cancers than in the population as a whole, because siblings share around 25 percent of their genes. "In our first round of analysis it looked as if childhood cancer does, in fact, contain a genetic component," reports chief epidemiologist Jørgen H. Olsen of the Danish Cancer Society. "Compared to people in general, siblings of young cancer patients actually had a 24 percent greater risk of developing cancer themselves."


‘Losing children to this disease is tragic’

But the picture changed completely when the researchers rearranged their data. "What we did was simply take a closer look at the individual diagnoses and exclude the few families in which children suffered from cancers that we positively know have a genetic background," says Falck Winther. The most common heritable cancer is retinoblastoma, a tumor in the retina, which is often detected within the first three years after birth; another is neurofibromatosis, which leads to tumors in the nervous system. Both these and a few other forms are caused by so-called dominant genetic mutations. In other words, they stem from inheriting a single copy of a faulty gene from one parent. When the epidemiological data were analyzed without these cases, siblings of cancer patients were at no greater risk for getting cancer than anyone else.

As Olsen points out, researchers are getting good handles on tracing the causes for the cancers that strike among adults. "For about a third of the cases there are well documented causes that can be traced back to the person's lifestyle or environment, he says. A host of risk factors including smoking, excessive exposure to ultraviolet radiation, viral infections and exposure to asbestos in the work place have been identified in various types of cancer. But because these "adult" risk factors do not apply to children, researchers have long leaned towards a genetic explanation. So-called recessive genetic mutations were suspected and sought after. In order for a recessive mutation to break through and cause disease one has to inherit the faulty gene from both parents. Hunting for these mutations is difficult since it calls for epidemiological analyses among siblings. The new Nordic study therefore has great value in pointing researchers away from genes and telling them to concentrate on outside factors.

Although childhood cancer is relatively rare, Falck Winther stresses its seriousness. "Losing children to this disease is tragic, and we are anxious to get a clearer picture of the causes in order to come up with preventive measures," she says. But where to look? While adult cancers have increased, the incidence of childhood cancer has remained stable in most Western countries at least since the nineteen forties, and this, says Olsen, points in the direction of factors that have not changed over the century. Of course this has to be combined with the limited time period leading up to disease and Olsen predicts that "much future research in the field will revolve around investigating conditions during pregnancy." The growth of the fetus, the hormonal environment in the uterus, viral infections and other diseases could be important. "Right now we are thinking along all these lines," says Olsen who will be planning how best to use his epidemiological tools to shed more light on the area.

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