One reason for decreased cancer incidence among people with Down syndrome

An extra copy of chromosome 21 causes the developmental disabilities associated with Down syndrome. This chromosome has 231 genes on it. An extra copy of each has dramatic effects on a person's development. Interestingly, a 2002 study of 18000 people with Down syndrome showed that cancer-related death is 90% lower in this population, as compared to the general population.

Dr. Sandra Ryeom, a vascular biologist at Children's Hospital Boston in Massachusetts, thinks she has found the reason for this phenomenon.¹ Her experiments showed that an extra copy of the DSCR1 gene (also known as RCAN1) suppresses the growth of blood vessels that supply malignant tumors. The growth of tumor blood vessels is called angiogenesis, and the process depends on vascular endothelial growth factor (VEGF). DSCR1 suppresses vascular endothelial growth factor via the calcineurin pathway.²

To test her theory, Dr. Ryeom took advantage of the Ts65dn mouse model for Down syndrome. This mouse has three copies for 104 out of the 231 genes on human chromosome 21, including DSCR1. She injected skin and lung cancer cells to see how tumors would grow in this experimental model. Amazingly, she saw 50% less tumor growth after 3-4 wks in the Ts65Dn mice. To see whether DSCR1 caused this effect, she also looked at tumor growth in mice engineered to have 3 copies of DSCR1, but 2 copies of all other genes. She observed 50% less tumor growth after 3-4 wks in this model, which showed that DSCR1 was sufficient to suppress tumor growth. The researchers also looked at Ts65dn mice that did not express DSCR1, and saw 25% less tumor growth. So DSCR1 is not necessary for the limited tumor growth observed in patients with Down syndrome.

The next step was to verify this effect in humans. Scientists used induced pluripotent stem (iPS) cells derived from the skin cells of people with and without Down syndrome. When injected into mice, iPS cells normally form teratomas, tumors made up of a variety of types of cells. iPS cells from normal patients gave rise to tumors that successfully created a system of blood vessels. But iPS cells from patients with Down's yielded tumors with blood vessels that budded but never developed fully.

The research may represent a potential cancer therapy, except that this gene affects normal as well as tumor blood vessel growth. So a drug that acted on DSCR1 to inhibit tumor blood vessel growth could have a negative effect on blood vessels throughout the body. Fortunately, these experiments opened the door to an exciting new area for research.

Check out this article on Scitable:

http://www.nature.com/scitable/topicpage/Trisomy-21-Causes-Down-Syndrome-318

¹Nayar, Anjali. Why people with Down's syndrome get fewer cancers. Naturenews. 20 May 2009.

²Baek, K.-H. et al. Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1. Nature advance online publication doi:10.1038/nature08062. 2009.