Scientists have localised the susceptibility gene for germ cell testicular cancer. A multinational study whose results were published this month (Nature Genetics 2000;24:197200) was set up in an attempt to establish the genetic basis of germ cell testicular cancer, which encompasses seminoma, teratoma, and mixed lesions, and makes up over 80% of testicular cancers.

Testicular germ cell tumours are the most prevalent form of cancer in men aged 15-40 years in western Europe. In the past 30 years, the incidence of testicular germ cell tumour in England and Wales has increased by more than 80%. It is currently unknown what percentage of this tumour is caused by an inherited genetic susceptibility, but estimates by the authors of the paper have put the figure as high as 20%.

Risk factors for testicular germ cell tumour include a history of undescended testis, testicular dysgenesis, infertility, and a previous history of such tumours. Testicular germ cell tumours are particularly susceptible to chemotherapy, and an early diagnosis in people at higher risk because of genetic susceptibility would therefore be beneficial.

Previous studies using polymorphisms - DNA sequences that have been identified to demarcate the location of the susceptibility gene - have shown that susceptibility to testicular germ cell tumour is not inherited in an autosomal manner. It has also been established that the risk to brothers of patients with testicular germ cell tumour of also developing such a tumour is higher (eightfold) than the risk to fathers or sons of patients (fourfold). The scientists hypothesised a model for X linked inheritance from these previous relative risk data. Subjects were recruited through the international testicular cancer linkage consortium and were selected from families with two or more cases of testicular cancer.

A genome-wide linkage study was performed. With this form of study, it is possible to detect the TGCT1 gene, as it has been named, without knowledge of its precise location in the entire genome. The search is for the polymorphic sequence and not the gene itself. Analysis of the DNA of subjects with testicular germ cell tumour yielded results that showed evidence of linkage on regions of chromosome Xq,27. Furthermore, statistical analysis showed significant evidence for a testicular cancer germ cell tumour susceptibility gene on chromosome Xq,27. The TGCT1 locus on the Xq,27 gene is associated with a higher risk of bilateral testicular germ cell tumour. TGCT1 may also predispose to undescended testis. Further work is planned ultimately to isolate TGCT1.