Genetic Variant Increases Testicular Cancer Risk Also Evolved To Protect Light Skin

Brett Smith for – Your Universe Online

Using a genomic analysis, a team of international researchers has identified a specific mutation responsible for a dramatic increase in the risk for testicular cancer.

The mutation is a single-base change to the genetic code that affects the activity of the p53 protein that is responsible for regulating the activity of a large number of genes, including those responsible for protection from UV rays – according to the team’s report in the journal Cell.

“Knowing the inherited genetics of cancer has great potential in medicine,” said study author Gareth Bond, a researcher at Oxford University’s Ludwig Institute for Cancer Research. “It can aid the development of tests to predict the risk of developing particular malignancies. It can also tell physicians about the likely prognosis of cancers, and inform therapeutic choices, improving management of the disease.”

About half of all cancers are affiliated with mutations in the p53 gene. Because the p53 protein activates a wide range of cancer-related signaling pathways, the study team hypothesized that cancer risk could be linked to genetic variations for p53-binding sites.

The single-based change, known as a single nucleotide polymorphism (SNP), was discovered after the team analyzed genetic databases containing nearly 63,000 SNPs in search of mutations that affect p53’s ability to turn on its target genes. The researchers were able to find one particular mutation that is very strongly linked to the risk of developing testicular cancer.

The SNP was found in the genetic code for a p53 response element that codes for a protein named KIT ligand (KITLG).

“It appears that this particular variant permits testicular stem cells to grow in the presence of DNA damage, when they are supposed to stop growing, since such damage can lead to cancer,” said study author Douglas Bell of the US National Institute of Environmental Health Sciences.

Next, the team performed an evolutionary genomic analysis that revealed that other SNPs that alter p53’s ability to bind its receptors have been lost by natural selection. The KITLG mutation not only slipped through the cracks, it has been “positively selected in the Caucasian gene pool.”

To explain why evolutionary forces would select for a cancer-causing mutation, the study authors noted that p53 is activated in certain cells of the skin after exposure to UV radiation, fueling the secretion of KITLG and causing pigment-making cells to multiply, increased melanin production. The result is a skin tan that protects from future exposure to the sun’s rays.

“Over the course of evolution, as humans migrated out of Africa into the dimly lit terrain of the north, they developed lighter skin, most likely to adapt to the lower levels of sunlight,” Bond explained. “Unfortunately, that adaptation also left their skin susceptible to UV damage. It is intriguing to speculate that the better version of the KITLG p53 response element is evolution’s compensation for that vulnerability. But it appears to come at a cost—which is a greater risk for testicular cancer.”

“I’d speculate that serious sun damage to skin would have posed a mortal threat to our early ancestors,” he added.