A gene important in the skin tanning process has been linked to a higher risk of testicular cancer in white males, according to a recent study conducted by scientists from the U.S. National Institutes of Health and the University of Oxford in England. Almost 80 percent of white males in the study carried a gene variant that resulted in an increased risk of testicular cancer of up to threefold.

This research is the result of an integrated analysis of data supported by laboratory research. Researchers suspected variations in a gene pathway controlled by the tumor suppressor gene p53 could have positive and negative effects on health.

“Gene variations occur naturally, and may become common in a population if they convey a health benefit,” said Douglas Bell, Ph.D., author on the paper and researcher at the National Institute of Environmental Health Sciences (NIEHS), part of NIH. “It appears that this particular variant could help protect light-skinned individuals from UV skin damage, like burning or cancer, by promoting the tanning process, but it permits testicular stem cells to grow in the presence of DNA damage, when they are supposed to stop growing.”

Bell explained that p53 stimulates skin tanning when ultraviolet light activates it in the skin. It must bind a specific sequence of DNA located in a gene called the KIT ligand oncogene (KITLG), which stimulates melanocyte production, causing the skin to tan.

To conduct the analysis, Xuting Wang, Ph.D., of NIEHS, co-author and lead bioinformatics scientist on the paper, led a data discovery expedition to comb through several different sets of data. The team selected potential leads from more than 20,000 p53 binding sites in the human genome, 10 million inherited genetic variations genotyped in the 1000 Genomes Project, and 62,000 genetic variations associated with human cancers identified in genome wide association studies (GWAS). The data sets were gathered through the  joint efforts of thousands of researchers worldwide.

“In the end, one variant in the p53 pathway was strongly associated with testicular cancer, but also, surprisingly, displayed a positive benefit that is probably related to tanning that has occurred as humans evolved,” Wang noted.

A group from the Ludwig Institute for Cancer Research at the University of Oxford, led by Gareth Bond, Ph.D., performed complex experiments to confirm the molecular mechanism that linked the gene variant with cancer and tanning.

“White males with a single nucleotide variation in KITLG, called the G allele, have the highest odds of having testicular cancer. In fact, the twofold to threefold increased risk is one of the highest and most significant among all cancer GWAS conducted within the past few years,” said Bond. “The high frequency of this allele in light skin individuals may explain why testicular cancer is so much more frequent in people of European descent than those of African descent.”

This research appears online in the journal Cell.