“Genes behind testicular cancer have been pinpointed for the first time, paving the way for a test to identify those at high risk of developing the disease,” the Daily Mail reported. It said that in two separate studies by British and American researchers, variants in chromosomes 5, 6 and 12 were found to be more common in men with testicular cancer than in healthy men.
These genome-wide association studies were well conducted. They have identified variants that are associated with an increased risk of developing testicular cancer. Testicular cancer is a rare disease and having these variants does not guarantee the disease will develop, but increases the risk that it will. In the future, it may be possible to screen people for testicular cancer and to determine who is at higher risk of developing it.
Where did the story come from?
This story is based on two studies published in the peer-reviewed journal Nature Genetics .
Both studies are genome-wide association studies that assessed the risk of testicular cancer. The first was carried out by Dr Elizabeth Rapley and colleagues from the Institute of Cancer Research and other academic and medical institutions across the UK. Their research was funded by the NHS and the Institute of Cancer Research, Cancer Research UK and the Wellcome Trust.
The second study was carried out by Dr Peter Kanetsky and colleagues from the University of Pennsylvania. This research was funded by the Abramson Cancer Center at the University of Pennsylvania, the Lance Armstrong Foundation and the US National Institutes of Health.
What kind of scientific study was this?
Both studies aimed to identify differences between the genetics of men with testicular cancer and those without it. Both were genome-wide association studies (a type of case-control study) that assessed DNA sequences of large numbers of men.
The UK-based research had two main components. In the first component, researchers analysed the genetic sequences at 307,666 points in 730 testicular cancer cases to see whether there was any variation compared with 1,435 controls. All the men who took part in the study were from the UK. To confirm their results, the researchers repeated the tests in another 571 testicular cancer cases and 1,806 controls.
The researchers analysed how these variants were linked to different subgroups of testicular cancer cases, in particular the men’s age when the cancer started. They also assessed whether the variants had effects on the risk of developing different types of testicular cancer (there are two types of testicular cancer, called seminoma and nonseminoma, depending on the type of cell that makes up the cancerous tumour). They also investigated whether the variants were associated with having a family history of testicular cancer, either unilateral or bilateral disease (one or both testicles) and cases of testicular maldescent (where the testicles fail to descend fully) compared with those with normal descent.
The second study had similar goals and methods. Researchers in the USA compared genetic material from 277 white, non-Hispanic testicular cancer cases and 919 white, non-Hispanic controls. This study was replicated in a separate group of 371 cases and 860 controls.
What were the results of the study?
In the first stage of the UK study, researchers found that variants on chromosomes 1, 4, 5, 6 and 12 were associated with a risk of testicular cancer. Three of these variants (on chromosomes 5, 6 and 12) were confirmed as being associated with a risk of cancer by the tests on the second set of cases and controls, with the strongest evidence from two variants on chromosome 12 (rs995030 and rs1508595). Men with the rs995030 variant were found to be 2.3 to 2.5 times more likely to develop testicular cancer than those without the variant. Men with rs1508595 were 2.5 to 2.7 times more likely to develop cancer. The risk was even greater for men who had two copies of these high-risk variants (homozygotes).
There was no difference in contribution of the variants on chromosomes 5, 6 and 12 to different types of testicular cancer (seminoma or nonseminoma) or cases with a family history of testicular cancer compared with those without. However, the variant rs4624820 on chromosome 5 had a stronger link with early-onset testicular cancer. The variants rs995030 and rs1508595 on chromosome 12 had stronger links with cancer in men who were older when they were diagnosed.
The researchers from the University of Pennsylvania confirmed these findings, noting the association between variants on chromosome 12 (within the KITLG gene) and the risk of testicular cancer. They also found associations with different variants on chromosome 12 (rs3782179 and rs4474514), both of which tripled the risk of developing testicular cancer.
What interpretations did the researchers draw from these results?
The researchers in the UK study concluded that men carrying two copies of all four high-risk variants are about four times more likely to develop testicular cancer than the general population. They say that the strong association between testicular cancer and two variants in chromosome 12 could be explained by the function of the KITLG gene (also known as stem cell factor). Previous studies support the involvement of this gene in associations with testicular cancer.
The US study confirmed that the KITLG gene is strongly implicated as a susceptibility gene in testicular cancer.
What does the NHS Knowledge Service make of this study?
These two separate genome-wide association studies suggest that the KITLG gene on chromosome 12 is strongly linked to the risk of testicular cancer. These are well-conducted studies and their results seem reliable. Both studies confirmed their results in separate cases and controls.
Some findings were surprising and there are several points to keep in mind when interpreting the results of these types of genetic studies:
- The UK researchers say that variants should be more strongly linked with disease in people with a family history of testicular cancer. The fact that the findings from this study show that they were not is surprising. They say that larger studies are needed to further investigate “this apparent absence of familial enrichment”.
- The four-fold increase in risk of testicular cancer that the newspapers quote refers to the possible increase in risk if people carry two copies of all four high-risk variants identified by the UK study. According to the UK researchers, only 0.7% of the population will be carriers of two copies of all four high-risk variants. Previous studies have reported that the worldwide incidence of testicular cancer is 7.5 men per 100,000. This varies considerably between countries and ancestry groups.
- These studies are important and may contribute towards the development of screening tests for testicular cancer. However, the researchers acknowledge that further studies are needed to refine these estimates before they can be used in clinical practice.
Having these variants does not guarantee the disease will develop, but increases the risk that it will. In the future, it may be possible to screen people for testicular cancer and to determine who has a higher risk of developing it.