4 June 2009
Testicular cancers - more specifically, testicular germ cell tumours (TGCT) - are the most common cancers in young men. There is evidence that genetic factors may play a more significant role than for many other types of cancer, with the risk of TGCT in the brothers of affected males increased by by 8-12 times (and as much as 75 times for identical twin brothers).
A new paper in Nature Genetics reports the identification of genetic factors associated with increased risk of testicular cancer from a small genome-wide association study (GWA). The US researchers compared DNA from 277 white men with TGCT with control DNA from 919 unaffected white men, and identified significant associations with several markers in the KITLG (c-KIT ligand or stem cell factor) gene region on chromosome 12 [Kanetsky PA et al. (2009) Nat Genet. May 31, Epub ahead of print]. A number of additional markers showed lower levels of significance, including some in the region of the SPRY4 (sprouty homolog 4) gene on chromosome 5, which has previously been implicated in the KIT–KITLG signaling pathway. Associations with TGCT were confirmed for selected markers from the KITLG and SPRY4 gene regions in an independent set of 371 TGCT cases and 860 controls. Possession of the higher-risk allele for each marker on chromosome 12 conferred a three-fold increased risk of testicular cancer, whilst homozygosity for the higher-risk allele conferred an overall increase in risk of 4.5-fold.
A second paper in the same journal also reports findings from GWAs for TGCT. The UK group looked at DNA from 730 TGCT cases and 1435 controls, and identified markers on several chromosomes. Replication in an independent data set of 571 cases and 1806 controls confirmed significant association between markers on chromosomes 5, 6 and 12 with risk of TGCT [Rapley EA et al. (2009) May 31, Epub ahead of print]. The strongest association was for markers in the KITLG gene region on chromosome 12; homozygosity for a higher-risk allele in this region was reported to confer a six-fold increased risk of testicular cancer, and approximately two-fold for homozygosity at the markers on chromosomes 5 and 6, which lie in the SPRY4 and BAK1gene regions respectively. Expression of the BAK1 gene (which encodes a regulator of apoptosis) in testicular germ cells is repressed by the KITLG–KIT pathway.
This new testicular cancer susceptibility gene on chromosome 12, KITLG, is highly plausible, given the role of the gene product. Kanestsky et al. note that the KITLG–KIT signalling pathway is involved in various key biological processes including the formation of germ cells (gametes) and male fertility, and that mutations in the KIT gene are common in some forms of testicular tumours. They propose that their findings may reveal some degree of shared genetic basis for TGCT and male infertility (for which an epidemiological association has been reported) and further suggest that the substantially higher observed incidence of TGCT in white males may relate to inherited variation at the KITLG locus, since the KITLG protein is also involved in determining the level of skin pigmentation.
Comment: The UK researchers are reportedly now seeking to recruit up to 3000 men who have had testicular cancer to participate in the study to identify more genetic risk factors – and, presumably, to validate those already reported in a larger data set and generate more robust estimates of the disease risk associated with each. Referring to the newly identified risk factors, Professor Mike Stratton of the UK Institute of Cancer Research (ICR), where the research took place, commented: “By combining these genetic risks with other known risk factors it may be possible in future to identify men who are at high risk of developing testicular cancer, particularly those who have a brother or father already affected by the disease. This may allow early detection or prevention” (see press release). However, the genetic risk factors identified in the two new papers do not by any means account for all the familial component of testicular cancer risk, and so although information about these risk factors may be able to improve current methods of risk prediction, they would not be very useful without information about other relevant risk factors.