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- 19 December 2013 12:36 pm , Vol. 342 , #6165
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Testicular Cancer May Be the Price Paid for Sun Protection
10 October 2013 4:15 pm
A genetic variant that increases the risk of testicular cancer may be favored by evolution because it helps protect those with fair skin from the sun’s damaging ultraviolet rays, according to a new study. The finding could account for white men being more susceptible than black men to this type of cancer. It may also explain why testicular cancer is so readily treatable.
Gareth Bond, a molecular biologist at the Ludwig Institute for Cancer Research in Oxford, U.K., and colleagues hit upon the unexpected tradeoff while studying inherited genes that influence cancer risk. They were especially interested in a gene known as p53, which is mutated in more than half of all cancers. The protein produced by this gene is a key defense for the cell—acting on a wide array of other genes to protect against many types of stress, including DNA damage and oxygen deprivation. It also protects against cancer, telling badly damaged cells to commit suicide. Mutations in p53, or in other genes with which it acts, prevent this order from being received, and damaged cells continue to reproduce, forming tumors.
Because cancers involving p53 are so common, Bond and his colleagues suspected that inherited mutations in the gene, or in genes it activates, could affect cancer risk. But such inherited mutations are hard to find, because they’re usually eliminated during evolution, he explains. In fact, it isn’t clear why they should persist at all.
In the new study, Bond and colleagues were looking in p53’s target genes for mutations that had managed to hang on. First, they pored through previously published genetic dragnets, looking for DNA changes in which a single building block, or nucleotide, is substituted for another. These variants, called single-nucleotide polymorphisms (SNPs, pronounced “snips”), are the route through which variations in traits such as hair and eye color, as well as many diseases, are often passed to future generations.
The researchers first checked the published databases for SNPs in the human genome that are known to be associated with cancer—some 60,000 possibilities. To see if any of these lay in genetic sequences on which the p53 protein acts, the investigators used data from several lines of healthy and cancerous cells subjected to various p53-activating treatments. This round resulted in 86 SNPs both linked to cancer and “living” in regions to which p53 attaches. Finally, the search, reported online today in Cell, narrowed down to one SNP in a DNA sequence strongly bound by p53. The sequence is an on-switch for a protein known as KIT ligand (KITLG); three previous studies have linked SNPs in this region with testicular cancer.
So why has this cancer-causing mutation stuck around? An evolutionary analysis showed the SNP had become more common, not less, as humans migrated northward out of Africa: It’s found in 80% of Caucasian Europeans, but in only 24% of people of African descent. Probably not coincidentally, testicular cancer is also four to five times more common in white men than in black men.
One way a seemingly deleterious mutation can become common over time in a group of people is if it also has a benefit that outweighs its harm, explains co-author Douglas Bell, a molecular biologist at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina. The benefit, the researchers suggest, is that under normal circumstances, KITLG protects pale skin against damage from sunlight. Previous research, some of it by members of the current team, had shown that KITLG triggers the production of pigment-producing cells called melanocytes in response to UV light. But the work hadn’t connected the dots between p53, its target DNA sequence, the activation of KITLG, and the production of melanocytes.
In the new study, Bond’s team exposed normal mice and mice missing p53 to UV radiation. Normal mice produced more than four times more melanocytes than did the p53 “knockout” mice. In the normal mice, UV treatment doubled the amount of KITLG produced, whereas the p53 knockouts couldn’t produce any. The results provide clear evidence that UV damage activates KITLG to trigger melanocyte production, and that the process is dependent on p53, the authors say. The variant uncovered in the study increases the degree to which p53 activates its target gene to stimulate cell production. But it also raises the risk that cells—malignant testicular cells, in this case—could be produced inappropriately.
“Of all the SNPs associated with cancer, this is the only one shown to respond to p53,” says Guillermina Lozano, a geneticist at the University of Texas MD Anderson Cancer Center in Houston who was not affiliated with the study. She adds that although the individual components of this cell-stimulating pathway were known, this study is the first to link the entire process.
The authors say that the study may also explain testicular cancer’s high cure rate—virtually 100% if the disease has not spread, and up to 90% even if it has. (The cyclist Lance Armstrong was cured even after the cancer had spread to his brain.) Most chemotherapies work by damaging the DNA of rapidly dividing cancerous cells, trying to rouse p53 to give the command to commit suicide. When they don’t work, it’s often because the cancer has found a way to cripple p53. Testicular cancer, however, is an unintended consequence of p53’s ability to stimulate, not call off, cell production. Because the protein is already functioning well in this context, its more common ability—halting the growth of other, unwanted cells—may also be easier to exploit, the researchers suggest.
“As early humans migrated northward out of Africa, losing skin pigmentation allowed them to retain more vitamin D in the dimly lit terrain. But those who were better able to repair UV damage had an advantage,” Bell says.
The increased risk of testicular cancer may have been an acceptable evolutionary tradeoff because the disease affects only men and usually occurs after they’ve had a chance to reproduce. Bond adds, “For our ancestors, protection from sun damage was critical to survival. For example, a bad burn can breach the skin’s protective barrier against infection, and our forebears had no antibiotics.”