Two new genome-wide association studies identify 30 new risk variants for testicular cancer. One study suggests that genes involved in transcription regulation during development and microtubule assembly promote development of the disease. The second study implicates genes involved in mitochondrial metabolism, germ cell maturation, and DNA damage repair.
Two new genome-wide association studies (GWAS) for testicular cancer more than double the number of variants linked to the disease and uncover more pathways that may promote cancer development. Further study of these variants and pathways may help researchers identify new treatment targets.
Genetics plays a large role in testicular cancer. A man is eight to ten times more likely to develop the disease if a brother has it, and previous GWAS have uncovered 27 loci that affect susceptibility.
Critics have complained that GWAS mainly find rare genes that have little impact on disease susceptibility, and they have argued that the studies haven't increased our understanding of how cancer arises. Testicular cancer is an exception, says Katherine Nathanson, MD, of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia. She notes, for instance, that GWAS for testicular cancer have demonstrated the surprising importance of genes involved in germ cell maturation and differentiation. However, the known susceptibility loci account for only 19% of the disease risk for brothers of men with the cancer, motivating researchers to search for more.
In one of the studies, researchers performed a GWAS on 3,206 patients with testicular cancer and conducted a meta-analysis on the two largest existing GWAS for the disease. Combining the results of the GWAS and the meta-analysis allowed the scientists to pinpoint 19 new risk loci.
Many GWAS variants lie outside genes, making it hard to assess their effects. To overcome this problem, the team used a technique known as in situ chromosome conformation capture to identify interactions between the risk loci (SNPs) and the promoter regions of specific genes, thus indicating which genes the SNPs are likely to be acting on. Several of these genes, such as GATA4 and ZFPM1, help control transcription during development, suggesting that this process may contribute to the disease. Other genes implicated in testicular cancer, including TEX14 and PMF1, take part in microtubule and chromosome assembly.
The findings “give additional support for the highly polygenic nature of testicular cancer, as well as giving us new insights into the biology underlying the associations at these loci,” says Clare Turnbull, MD, PhD, of The Institute of Cancer Research in London, UK, a co-author on both studies.
In the second study, researchers performed a meta-analysis of five GWAS for testicular cancer, identifying 12 risk loci. The analysis pointed to genes such as ZPF42 and TFCP2L1 that are involved in germ cell maturation, as well as TKTL1, which is important for mitochondrial metabolism. The researchers also uncovered genes crucial for DNA damage repair and kinetochore function. “We are continuing to identify loci with major effects” in testicular cancer, says Nathanson, senior author on the second study.
Together, the two studies increased the number of risk variants for testicular cancer by 30. One variant, located in the promoter for MAP2K1, a gene involved in the KIT–MAPK pathway, turned up in both studies.
Researchers don't know if any of the SNPs will lead to the identification of treatment targets. However, Nathanson says that they may be clinically useful. Patients with conditions such as undescended testicles or infertility are at higher risk of testicular cancer. Testing for the SNPs could indicate which patients are particularly susceptible and may be candidates regular screening.
Eliezer Van Allen, MD, of Dana-Farber Cancer Institute in Boston, MA, who wasn't connected to either study, describes the results as exciting. “By doing a much larger analysis than was done previously, they were able to find more risk variants.” He says that researchers now need to characterize the variants, using techniques such as animal studies, and determine how they promote disease. –Mitch Leslie