A meta-analysis of nearly 200,000 men has revealed 22 new genetic locations that could be susceptible to inherited testicular germ cell tumors (TGCT). The findings increase by 40% the number of regions known to be associated with this type of cancer. The multi-institutional meta-analysis was conducted by researchers from the international TEsticular CAncer Consortium (TECAC), led by Katherine L. Nathanson, MD, deputy director of Penn’s Abramson Cancer Center and the Pearl Basser professor of BRCA-related research in the Perelman School of Medicine at the University of Pennsylvania.
“This latest set of genetic locations is adding to our understanding of the inherited drivers of testicular cancer, as we look to improve screening among men who may be at high risk,” Nathanson said. “Although this cancer is curable, identifying these men earlier can help save them from having to undergo certain treatments, such as chemotherapy, which can have late and unwanted complications.”
Nathanson and colleagues reported on their findings in Nature Communications, in a paper titled, “Identification of 22 susceptibility loci associated with testicular germ cell tumors.” In 2017, TECAC reported an additional 12 loci. The new study brings the total number to 78. The researchers suggest the results could help doctors understand which men are at the highest risk of developing the disease, and inform on future screening.
Germ cell tumors account for 95% of testicular cancer cases. TGCTs are the most common cancer in the United States and Europe in white men between the ages of 20 and 39 years. The number of cases has continued to rise over the past 25 years in white men and more recently in Latino men. “ … incidence of TGCT has doubled over the past 20 years,” the authors wrote. But “despite the high heritability of TGCT, estimated at 37–49%, CHEK2 is the only moderate penetrance gene in which pathogenic variants have been associated with risk of TGCT.”
Genome-wide association studies (GWAS) have been more successful, identifying common variations associated with risk of the disease. Nathanson and TECAC teams have used the method to find chromosome loci that contain variants associated with an increased risk of germ cell tumors. For their newly reported study, the TECAC researchers analyzed genetic data from 10,156 testicular germ cell tumor cases and 179,683 controls, in the largest GWAS of TGCT to date.
The study revealed 22 novel loci. When taken together, the results could explain 44% of the father-to-son familial risk for testicular cancer, the authors said. Men with a high polygenic risk score (PRS) had a significantly increased disease risk compared to men at the median score. “Men in the 95th percentile of the PRS have a 6.8-fold increased disease risk compared to men at the median PRS, and these men have a 3.4% lifetime risk as compared to 0.4% in the general population,” the authors wrote. “The PRS for TGCT contains fewer SNPs than those available for most other common cancers, yet with a larger effect.”
Beyond the statistical significance of the new loci, the study also demonstrated two relevant biological pathways tied to disease susceptibility, male germ cell development and chromosomal segregation during cell division. When these pathways go awry, they lead to TGCT tumorigenesis.
“Results from our investigation provide further understanding of the genetic architecture of TGCT, enhance comprehension of the biology of male germ cell development, and highlight biological pathways specifically important to TGCT that are not noted in other cancers,” the authors wrote. “Importantly, we have established a polygenic risk score that identifies men at highest risk of disease, which could be potentially applied in men with other risk factors, such as [undescended testes] or infertility, to be targeted for early detection and disease mitigation.”
Next, researchers will begin to further investigate the increase in TGCT cases observed among Latino men and if the genetic variants observed in mostly white men also exist in that population.