By deleting a gene regulatory element upstream of well-known cancer gene Myc, a team of researchers from Finland and Sweden have prevented the formation of intestinal tumors in a mouse model.
In addition to pinpointing a potential new target for cancer therapy, the results show that genome-wide association studies (GWAS) can be used to find regulatory elements in that genome that play a role in specific diseases.
In a paper published this week in Science (1), the team reported on their study of the SNP that is tied to more human cancers than any other variant: SNP rs6983267. To see if it played a role in the disease, the team generated mice that lacked the region Myc-335 in the genome that included this particular SNP. Myc-335 sits 300 kb upstream of Myc promoter and was thought to be a gene enhancer.
To their surprise, Myc-335-deficient mice were healthy and expressed relatively normal levels of Myc. “We did expect that [deleting Myc-335] would have a major impact on normal function of the intestine, but it turns out that you can remove this element and the mice are fine,” said study author Jussi Taipale, a professor of medical sciences at the University of Helsinki in Finland.
Because SNPs identified through GWAS confer small effects—associated with only 10–20% increases in risk—to study the function of those variants individually would require hundreds or thousands of mice. That’s partly why the prospect of GWAS follow-up studies have proven daunting. In contrast, deleting an entire regulatory element in which those variants are located might have a much stronger impact, as this study demonstrates.
Indeed, when the group crossed Myc-335 deficient mice with mutant mice prone to intestinal tumorigenesis, the scientists found that the offspring lacked the regulatory element and develop dramatically fewer tumors compared to a control group.
“The genetic evidence from human already pointed out that this element is important in tumorigenesis,” noted Taipale. “We were surprised at how big the effect was, that it has a major impact.”
Now, Taipale plans to analyze the other GWAS regions to understand which other regulatory elements are important for intestinal tumorigenesis. As with this study, the group will build a case for each regulatory element before moving into mouse models. “We first have to find the SNP that most likely is causative, not just one associated with risk,” said Taipale.
Computational tools, such the Enhancer Element Locator software developed by his team, help pinpoint the gene regulatory elements close to tag SNPs identified in GWAS. Then researchers can validate those findings in cell culture or mouse studies.
1. Sur, I. K., O. Hallikas, A. Vähärautio, J. Yan, M. Turunen, M. Enge, M. Taipale, A. Karhu, L. A. Aaltonen, and J. Taipale. 2012. Mice lacking a myc enhancer that includes human SNP rs6983267 are resistant to intestinal tumors. Science (November).