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People with Down syndrome appear to have genes that protect against cancer
By Lone Frank

An extra copy of chromosome 21 causes mental retardation and physical malformations such as characteristic facial features in patients with Down syndrome. A new study shows that while Down patients run an increased risk of leukemia, they have a much lower incidence of many other forms of cancer, including breast cancer. Their analysis led Danish researchers to suggest a search of chromosome 21 for genes that may protect against cancer.

Illustration of part of a karyotype showing the extra chromosome 21.

"We were completely surprised and did not expect to find such a general effect," says study leader Henrik Hasle, who is a pediatrician at Skejby Sygehus near Århus. He set out to do an in-depth investigation of leukemia and only looked at other cancers because earlier case reports had mentioned a peculiar absence of solid tumors in Down patients. In their analysis of the medical history of almost 3,000 patients, Hasleís group took advantage of a unique Danish resource. The country is home to a host of centralized health care databases that contain detailed information that can readily be cross-linked because all patients are registered with their permanent personal identification number.

Since 1961, every Dane born with a major chromosomal abnormality has been registered in the Danish Cytogenetic Register. The Cancer Register contains information on diagnosis and treatment of all Danish cancer patients since 1943. Combining these two data sets showed that while people with Down syndrome are 18 times more likely to suffer from leukemia, their overall risk for solid tumors is half that of the general population. "For breast cancer the tendency was startlingly clear. We saw no cases of breast cancer among our patients, whereas statistically we find seven in an age-matched control group," cancer epidemiologist Inge Haunstrup Clemmensen, of the Danish Cancer Society, reports. She says the observed decrease in solid tumor frequency is too pronounced to be explained by non-specific effects such as a healthier life style among Down patients or less exposure to carcinogens in the environment. Similarly, hormonal differences among Down patients would not account for the decrease in breast cancer frequency.

The researchers suggest the extra chromosome 21 lies at the heart of the matter. Cancer is generally a genetic disease in which several mutations make individual cells escape normal growth control and start dividing at their own pace. As for leukemia, chromosome 21 could contain genes specifically involved in promoting this development in blood cells. Scientists are already studying the AML-1 gene, which is located on chromosome 21 and mutated in 20 percent of children with leukemia. The gene is involved in blood cell development and an abnormally high activity could play a role in leukemia. Indeed, measurements of the activity of several genes indicate that Down patients generally experience a 50 percent higher activity of genes on chromosome 21. And with regard to the low incidence of solid tumors, Hasle speculates that, "It could stem from high-level activity of tumor suppressor genes on this chromosome, conferring protection against cancerous changes."

The high level of tumor suppressor genes on chromosome 21 could confer protection against some cancers.

Geneticist Karen Brøndum, of Copenhagenís Kennedy Institute, calls this, "an interesting hypothesis that is definitely worth pursuing." She points out how recent studies show that cancers of the breast, lung and mouth are sometimes associated with loss of certain regions of chromosome 21, which indicates that these regions contain tumor suppressor genes. But the hunt for specific genes may not be easy. According to cancer biologist Per Guldberg of the Danish Cancer Society, tumor suppressors are a motley crew with many different structures and functions. This means that even with the soon-to-be-completed map of chromosome 21, scientists cannot simply look for specific DNA sequences. "Tumor suppressors are generally identified by being absent or mutated in cancer cells and this entails extensive laboratory analysis," he explains.

As an epidemiologist, Hasle will not personally take the next step, moving this research into the lab, but he hopes to inspire those who can. "Clearly, better knowledge of the molecular processes involved in various types of cancer is instrumental in working out how to treat and prevent the disease," Hasle says. And he is pleased to report the first informal contacts from clinical researchers interested in using the Down study as a starting point for molecular investigations.

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Hasle, H., Clemmensen, I.H. & Mikkelsen, M. Risks of leukaemia and solid tumours in individuals with Down's syndrome. Lancet 355,165-169 (January 15, 2000).

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