Susceptibility alleles for testicular germ cell tumour: a review

Family history is among the strongest and most consistent of the risk factors for testicular germ cell tumour (TGCT). Brothers of affected cases have an 8- to10-fold relative risk and fathers/sons have a risk between four and sixfold. The familial relative risk of TGCT is higher than for most other cancer types, which rarely exceeds four. The high relative risk suggests that inherited susceptibility to TGCT may account for a substantial fraction of TGCT cases. The search for TGCT susceptibility genes has proven difficult and a recent genome-wide linkage study for TGCT susceptibility loci demonstrated no statistically significant regions of linkage with all LOD scores less than two. Moreover, a previous report of linkage to a region on Xq27 was not replicated. The results from genetic linkage analysis demonstrate that TGCT susceptibility is likely to be due to several genes, each with a modest effect on disease risk. The Y chromosome, which cannot be analysed by genetic linkage, carries a number of testis- and germ cell-specific genes. We recently demonstrated that a deletion on the Y chromosome known as 'gr/gr' is a rare, low-penetrance allele that is associated with susceptibility to TGCT. Based on the evidence from the linkage search the 'gr/gr' deletion represents one of possibly many TGCT susceptibility alleles, and new and emerging technologies will be employed in future work to identify these genes.