Multiple studies have indicated that a SNP in the FGFR2 gene can increase the risk for breast cancer. Results published online this week in the open-access journal PLoS Biology show how.It turns out that the riskier version of this SNP increases the amount of the FGFR2 protein that is made by cells, which can stimulate cells to grow – and increases the chance that they will proliferate out of control and lead to cancer.Though the number of genome wide association studies is growing every day, very few of these studies have been able to explain why the SNPs they find are associated with a particular disease. Understanding how SNPs impact the biology of cancer and other common diseases will be critical for developing new treatments.The FGFR2 gene encodes a protein that is inserted through the surface of cells where it acts as a receptor for certain growth factors. A growth factor is a chemical signal in the body that can tell cells to divide, move around, or differentiate into more specialized types of cells.While several genetic mutations have been found that confer a high risk for breast cancer (most famously BRCA1 and BRCA2), these known genetic changes are actually relatively rare. There are probably many more common genetic changes that on their own don’t pose much of a risk, but in certain combinations can cause disease. The SNP in FGFR2 was one of the first of these common variants to be found.On average, a woman’s chances of developing breast cancer some time during her life are one in eight. Having two copies of the G version of SNP rs1219648 (instead of the most common genotype: AG) increase her chances to about one in six. Two copies of the A version of this SNP, on the other hand, reduce a woman’s chances to about one in 10. (These numbers apply only to women with European ancestry. 23andMe customers can learn more in My Gene Journal (now called Health and Traits).)
Meyer et al showed that the cells of women who had two copies of the G version of rs1219648 expressed significantly more FGFR2 than women with two copies of the A version (the study actually looked at another SNP that is thought to be universally linked to rs1219648).It’s known that in 5 to 10% of breast cancers, the FGFR2 gene is turned on at unusually high levels. And laboratory experiments have shown expressing extra FGFR2 in cells can cause them to take on cancer-like traits.When they investigated further, the researchers found that the G version of rs1219648 was associated with increased expression of FGFR2 because the versions of two SNPs (located very near rs1219648) that are inherited along with the G version of rs1219648 have a greater affinity for DNA-binding regulatory proteins that help turn on the FGFR2 gene.Meyer et al believe that theirs is the first study to address the function of the SNPs associated with breast cancer.“Our study demonstrates that SNPs identified by whole-genome scans can be used as valid starting points for studying the underlying biology of cancer,” the authors write.Like many of the SNPs found in genome wide association studies, rs1219648 and other SNPs in FGFR2 that regulate the binding of regulatory proteins are in a non-coding part of the gene called an “intron”. Many other SNPs found in these types of studies are in non-coding regions of the genome located between genes.The authors speculate that their finding that SNPs in non-coding parts of the DNA can regulate gene expression will be a common theme.