Genetic Predisposition to Testicular Cancer
Family history is a well documented risk factor for testicular cancer. If a man has a brother who has suffered testicular cancer, his risk of developing the disease is 8-10 fold increased compared to a man without any family history of disease. If a man has a father or son with the disease, the increase in risk is 4-6 fold. These risks are much higher than the equivalent risks for most other cancer types (typically 2-3 fold). As a result, in around two percent of cases, men report another first degree relative (father, brother or son) affected with the disease. These observations indicate that genes are important in causing testicular cancer.
At The Institute of Cancer Research, we have been undertaking several studies to identify genes that increase the risk of developing testicular cancer. In order to conduct these studies, we have been collecting DNA samples and information from a large series of men with testicular cancer, with and without a family history of the disease. These samples have been used to successfully identify genetic factors that increase the risk of developing testicular cancer.
In 2005 we identified a region on the Y chromosome known as ‘gr/gr’ that, when deleted (or missing), gives a two- fold greater risk of developing testicular cancer1.
In 2009 we identified three regions on chromosomes 5, 6 and 12, variants at which increase the risk of developing testicular cancer2. This year (2010) we identified a further three regions associated with developing testicular cancer which lie on chromosomes 5, 9 and 123. To identify these regions, we examined approximately 300,000 different genomic variants in > 1000 men with testicular cancer and > 5000 controls (apparently unaffected individuals). We then double-checked our findings in a further 670 men with testicular cancer and >3500 controls.
Three of these variants are near genes involved in a the KIT signalling pathway – this is important for the survival and development of early testicular cells (germ cells). Two of the variants relate to genes which are important in maintaining the correct length of the ends of chromosomes, which are called telomeres. One variant is near the DMRT1 gene, which is pivotal in sex determination and has been implicated in the development of testicular cancer in mice.
By combining these genetic risk factors with other risk factors it may be possible in the future to identify men who are at high risk of developing testicular cancer, which may allow early detection or prevention.
However, this is not the end of the research. Our studies have demonstrated that several other genes and genetic variants must exist, which likewise increase the risk of developing testicular cancer. Our aim is to identify all these variants, to understand how they interact and to gain a better understanding of the biology of this disease. We are looking to recruit 3000 men who have had testicular cancer to participate in our study.
References
1. Nathanson,K.L. et al. The Y deletion gr/gr and susceptibility to testicular germ cell tumor. Am. J. Hum. Genet. 77, 1034-1043 (2005).
2. Rapley,E.A. et al. A genome-wide association study of testicular germ cell tumor. Nat. Genet. 41, 807-810 (2009).
3. Turnbull,C. et al. Variants near DMRT1, TERT and ATF7IP are associated with testicular germ cell cancer. Nat. Genet. 42, 604-607 (2010).
