protection at a price. a genetic defense against sun damage increases the risk of testicular cancer.
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a genetic variant that increases the risk of testicular cancer may be favored by evolution because it helps protect people with fair skin against the harmful ultraviolet rays of the sun, according to a new study. The finding could explain the white men are more sensitive than black men with this type of cancer. It may also explain why testicular cancer is so easily treatable.
Gareth Bond, a molecular biologist at the Ludwig Institute for Cancer Research in Oxford, UK, and his colleagues hit on the unexpected compromise in the study of hereditary genes that influence cancer risk. They were particularly interested in a gene called p53, which is mutated in more than half of all cancers. The protein produced by this gene is a key defense for the action cell on a wide range of other genes to protect against many kinds of stress, including DNA damage and oxygen deprivation. It also protects against cancer, saying severely damaged cells to commit suicide. Mutations in p53, or other genes with which it acts, prevent the order 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 genes it activates, could affect cancer risk. But these inherited mutations are hard to find because they are usually eliminated during evolution, he said. In fact, we do not know why they should persist at all.
In the new study, Bond and his colleagues were looking in the p53 target genes for mutations who had managed to hang on. First, they pored through genetic dredges previously published, looking for DNA changes in which a single building block or nucleotide is substituted for another. These variants, called single nucleotide polymorphisms (SNPs, "shears" pronounced) is the way in which changes in traits such as hair and eye color, as well as many diseases are often passed on to future generations.
The researchers first verified the published databases for SNPs in the human genome that are known to be associated with a cancer-about 60,000 possibilities. To see if any of these lay in genetic sequences where acts of p53 protein, the researchers used data from several lines of healthy and cancerous cells subjected to various p53-activated treatments. This tour led to 86 SNPs linked to cancer and as "living" in regions where p53 tie. Finally, research, today announced online in Cell reduced to a SNP in a DNA sequence strongly bound p53 . The sequence is a switch to a protein known kit ligand (KITLG); Previous studies have linked three SNPs in this region with testicular cancer.
So why has this mutation causing cancer stuck around? An analysis of the evolution showed the SNP had become more common, not less, humans have migrated north of Africa: It is found in 80% of white Europeans, but in only 24% people of African descent. Probably not coincidentally, testicular cancer is four to five times more common in white men than in black men.
One way apparently deleterious mutation can become common over time in a group of people is if it also has an advantage that outweighs the bad, says co-author Douglas Bell, biologist molecular to the National Institute of environmental health sciences in Research Triangle Park, North Carolina. The advantage, the researchers suggest, is that in normal circumstances, protects KITLG pale skin against sun damage. Previous research, some of them by members of the current team, showed that KITLG triggers the production of pigment-producing cells called melanocytes in response to UV light. But work has not connected the dots between p53, the target DNA sequence, enabling KITLG, and production of melanocytes.
In the new study, the Bond team exposed mice and normal mice missing p53 to UV radiation. Normal mice produced more than four times that melanocytes made the p53 mice "knockout". In normal mice, the UV treatment doubled the amount of KITLG product, while p53 KO could not produce any. The results clearly show that active KITLG UV damage to trigger the production of melanocytes, and that the process depends on p53, the authors say. The study covered the variant increases the degree to which its active p53 target gene to stimulate the production of cells. But it also raises the risk that malignant testicular cells-cells, in this case could be produced inappropriately.
"Of all the SNPs associated with cancer, this is the only indicated in response to p53," said Guillermina Lozano, a geneticist at the University of Texas MD Anderson Cancer Center in Houston who was not affiliated in the study. She adds that although the individual components of this pathway by stimulating cells were known, this study is the first to connect the whole process.
the authors say that the study could also explain high cure testicular cancer rates almost 100% if the disease has not spread, and up to 0%, although it has. (the cyclist Lance Armstrong has been cured even after the cancer had spread his brain.) most of chemotherapy work by damaging the DNA of cancer cells divide rapidly, trying to wake p53 to give the command to commit suicide. When they do not work, it is often because the cancer has found a way to paralyze p53. testicular cancer, however, is an unintended consequence of the ability of p53 to stimulate, not call off the production cells. Because the protein is already working well in this context, its stop-capacity growth in other, more frequent unwanted cells can also be easier to exploit, the researchers suggest.
"As early humans migrated north on Africa, loss of pigmentation of the skin allowed them to retain more vitamin D in the dimly lit ground. But those who were better able to repair UV damage had an advantage, "says Bell.
The increased risk of testicular cancer may have been an evolutionary compromise acceptable because the disease only affects men and occurs usually after they have had a chance to reproduce. Bond added: "For our ancestors, protection against sun damage is essential to survival. For example, poor combustion may violate the protective barrier of the skin against infection, and our ancestors were no antibiotics. "
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