Four newly identified genetic variants are associated with an increased risk of testicular cancer, according to a new study that examined the genomes of over 13,000 men. The discovery of these genetic variations could ultimately help researchers to better understand which men are at high risk and allow for early detection or prevention of the disease.
“As we continue to cast a wider net, we identify additional genetic risk factors, which point to new mechanisms for disease,” said Katherine L. Nathanson, MD, of the Perelman School of Medicine at the University of Pennsylvania. “Certain chromosomal regions, what we call loci, are tied into testicular cancer susceptibility, and represent a promising path to stratifying patients into risk groups—for a disease we know is highly heritable.”
Testicular cancer is relatively rare; however, incidence rates have doubled in the past 40 years. It is also highly heritable. If a man has a father or son with testicular cancer, he has a four- to sixfold higher risk of developing it compared to a man with no family history. That increases to an eight- to 10-fold higher risk if the man has a brother with testicular cancer.
Tapping into three genome-wide association studies (GWAS), Nathanson and other researchers analyzed 931 affected individuals and 1,975 controls. They confirmed the results of their analysis in an additional 3,211 men with cancer and 7,591 controls. The meta-analysis revealed that testicular germ cell tumor (TGCT) risk was significantly associated with markers at four loci—4q22, 7q22, 16q22.3, and 17q22, none of which have been identified in other cancers. Additionally, these loci pose a higher risk than the vast majority of other loci identified for some common cancers, such as breast and prostate.
This meta-analysis was reported in Nature Genetics (2013; doi:10.1038/ng.2634).
“This analysis is the first to bring several groups of data together to identify loci associated with disease,” said Nathanson, “and represents the power of combining multiple GWAS to better identify genetic risk factors that failed to reach genome-wide significance in single studies.”
The team also explains how the variants associated with increased cancer risk are the same genes associated with chromosomal segregation. The variants are also found near genes important for germ cell development. These data strongly supports the notion that testicular cancer is a disorder of germ cell development and maturation.
“TGCT is unique in that many of the loci are very good biological candidates due to their role in male germ cell development,” said Nathanson. “Disruptions in male germ cell development lead to tumorigenesis, and presumably also to infertility. These conditions have been linked before, epidemiologically, and genes implicated in both of our prior studies, but this study reinforces that connection.”