Third Gene Copy Is a Charm

By Greg Miller
ScienceNOW Daily News
2 January 2008

Reports stretching back half a century have suggested that people with Down syndrome may have a reduced risk of breast, colon, and other cancers. The reason has been a mystery, but some researchers suspect it has to do with one or more of the genes on chromosome 21, which people with Down syndrome have three copies of instead of the normal two. A new study backs that idea, linking a gene that is triplicated in Down syndrome to a lower risk of colon cancer in mice.

Geneticists Thomas Sussan of the Johns Hopkins Bloomberg School of Public Health and Roger Reeves of the Johns Hopkins School of Medicine, both in Baltimore, Maryland, and their colleagues mated mice prone to colon cancer with mice commonly used to model Down syndrome. These mice have extra copies of 108 genes--about half as many triplicated genes as in Down syndrome. Offspring that inherited the triplicated genes and the genetic susceptibility to cancer had only half the number of intestinal tumors as their cancer-prone parents, and the tumors that did develop were smaller, the team reports in the 3 January issue of Nature.

Additional experiments with several other mouse strains suggested that a gene called Ets2--whose human counterpart is triplicated in people with Down syndrome--accounts for much of the protection. Ironically, Reeves says, Ets2 was previously identified as a cancer promoter. He can't explain why having an extra copy of the gene would produce the opposite effect. "I think this is going to be a fairly complex thing to work out," Reeves says, adding that Ets2 encodes a transcription factor that influences the activity of at least 200 other genes.

The counterintuitive finding that a gene that promotes cancer in some contexts may repress it in others could have important implications for understanding, and ultimately treating, cancer in the general population, says geneticist David Threadgill of the University of North Carolina, Chapel Hill. "I think we have to reevaluate how we look at a lot of these cancer-associated genes."

Related site

Basic information about Down syndrome from the National Institutes of Health