GWAS Increases Genetic Loci Linked to Hereditary Testicular Cancer by 40%

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A meta-analysis of nearly 200,000 men revealed 22 new genetic locations that may be susceptible to hereditary testicular germ cell tumors (TGCT). The results increase the number of regions known to be associated with this type of cancer by 40%. 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 Professor Pearl Basser of BRCA-related research in the Perelman University of Pennsylvania School of Medicine.

“This latest set of genetic locations adds to our understanding of inherited factors in testicular cancer, as we seek to improve screening in men who may be at high risk,” Nathanson said. “Although this cancer is curable, identifying these men earlier can save them from having to undergo certain treatments, such as chemotherapy, which can have late and unwanted complications.”

Nathanson and his colleagues reported on their findings in Nature Communication, in an article entitled “Identification of 22 susceptibility loci associated with testicular germ cell tumors”. In 2017, TECAC reported 12 additional loci. The new study brings the total to 78. The researchers suggest the findings could help doctors understand which men are most at risk of developing the disease and inform about future screening.

Germ cell tumors account for 95% of testicular cancer cases. TGCT is the most common cancer in the United States and Europe in white males between the ages of 20 and 39. The number of cases has continued to increase over the past 25 years among white men and more recently among Latino men. “… The incidence of TGCT has doubled over the past 20 years,” the authors wrote. But “despite the strong heritability of TGCT, estimated at 37-49%, CHEK2 is the only moderate penetrance gene in which pathogenic variants have been associated with the risk of TGCT”.

Whole genome association studies (GWAS) have been more successful, identifying common variations associated with disease risk. The Nathanson and TECAC teams used the method to find chromosomal loci that contain variants associated with an increased risk of germ cell tumors. For their recently published study, TECAC researchers analyzed genetic data from 10,156 testicular germ cell tumor cases and 179,683 controls, in TGCT’s largest GWAS to date.

The study revealed 22 new loci. Taken together, the results could explain 44% of the father-son family risk of testicular cancer, the authors said. Men with a high polygenic risk score (PRS) had a much higher risk of disease than men with the median score. “Men in the 95th percentile of the PRS have a 6.8 times greater risk of disease than men in the median PRS, and these men have a lifetime risk of 3.4% compared to 0.4% in the general population. », Wrote the authors. “The PRS for TGCT contains fewer SNPs than those available for most other common cancers, but with a greater effect.”

Beyond the statistical significance of the new loci, the study also demonstrated two relevant biological pathways related to disease susceptibility, male germ cell development and chromosome segregation during cell division. When these pathways go wrong, they lead to TGCT tumorigenesis.

“The results of our investigation provide a better understanding of the genetic architecture of TGCT, improve our understanding of the developmental biology of male germ cells and highlight biological pathways of particular importance for TGCT that are not observed. in other cancers, ”the authors wrote. “It is important to note that we have established a polygenic risk score that identifies men at highest risk for disease, which could potentially be applied to men with other risk factors, such as [undescended testes] or infertility, to be targeted for early detection and mitigation of disease. “

Next, researchers will begin to investigate further the increase in cases of TGCT seen in Latino men and whether the genetic variants seen in most white men also exist in this population.


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