Using a mouse model, researchers at Johns Hopkins and Ohio State University discovered that some copies of a specific gene can influence the severity of colon cancer. They explain, in the journal Nature, how trisomy 21 (Down syndrome in humans) can hold back tumor growth.
Roger H. Reeves, Ph.D., professor of physiology, McKusick-Nathans Institute of Genetic Medicine, Hopkins, said “We took a new approach to a 50-year-old debate about whether people with Down syndrome develop cancer less often than other people. Studying the genetic differences associated with Down syndrome has revealed a new way of thinking about repressing cancer growth in everyone.”
The team began with a mouse model that carries a partial copy of chromosome 21 as is seen in Down syndrome (trisomy 21) containing 108 genes. These trisomic mice where crossed with mice that carry a mutation that causes intestinal tumors, like those seen in human colon cancers. The trisomic, colon cancer mice had 44% fewer intestinal tumors than the colon cancer mice that did not have the extra 108 genes.
They then repeated the genetic crosses using another mouse model of Down syndrome, one that carried extra copies of just 33 of the genes on chromosome 21. They found that the mice with three copies of the 33 genes had 50% fewer tumors compared to the mice with the standard two copies. The other mice, those with only one copy of these 33 genes, had twice the usual number of tumors.
Reeves said “Not only does having an extra copy of one or more of these genes repress tumor formation, it turns out that missing a copy enhances tumor growth-this was really surprising.”
Taking a closer look at the 33 genes to identify a probable cause for the dose-specific relationship with tumor growth, the researchers concentrated on one gene, Ets2, which has already been linked as a cause of cancer. However, some research suggested that Ets2 activity might be involved in pathways that cause cells to die.
The scientists then repeated their genetic crosses with mice that had one, two or three copies of the Ets2 gene only. They also found that mice that were trisomic for 33 genes, including Ets2, had a smaller number of tumors, but the mice which were trisomic for 32 of these genes, but had the normal two copies of Ets2, had similar tumor numbers to the control mice (the non-trisomic ones). While the mice with only one copy of Ets2 had more tumors.
Reeves said “These results support studies concluding that people with Down syndrome get fewer cancers of many types. While we’ve only shown this effect with Ets2 and a particular type of colon tumor in mice, we think that the human Ets2 gene might contribute to resistance toward other types of cancer, based on what happens in Down syndrome.”
Michael Ostrowski, an Ohio State cancer researcher and Ets2 expert who developed the mouse models used in this study, said “Our findings are significant because they broaden the definition of an ‘oncogene’ or ‘tumor suppressor gene’ to include the effect of gene dosage. They also suggest that finding ways to increase the expression of genes such as Ets2 might lead to a new strategy for treating or controlling cancer.”
“Trisomy represses ApcMin-mediated tumours in mouse models of Down’s syndrome”
Thomas E. Sussan, Annan Yang, Fu Li, Michael C. Ostrowski & Roger H. Reeves
Nature 451, 73-75 (3 January 2008) | doi:10.1038/nature06446
Written by – Christian Nordqvist