Familial testicular germ cell tumors in adults: 2010 summary of genetic risk factors and clinical phenotype

Abstract

Familial aggregations of testicular germ cell tumor (FTGCT) have been well described, suggesting the existence of a hereditary TGCT subset. Approximately 1.4% of newly diagnosed TGCT patients report a positive family history of TGCT. Sons and siblings of TGCT patients have four- to sixfold and eight- to tenfold increases in TGCT risk respectively. Segregation analyses suggest an autosomal recessive mode of inheritance. Linkage analyses have identified several genomic regions of modest interest, although no high-penetrance cancer susceptibility gene has been mapped yet. These data suggest that the combined effects of multiple common alleles, each conferring modest risk, might underlie familial testicular cancer. Families display a mild phenotype: the most common number of affected families is 2. Age at diagnosis is 2-3 years younger for familial versus sporadic cases. The ratio of familial seminoma to nonseminoma is 1.0. FTGCT is more likely to be bilateral than sporadic TGCT. This syndrome is cancer site specific. Testicular microlithiasis is a newly recognized FTGCT component. Candidate gene-association studies have implicated the Y chromosome gr/gr deletion and PDE11A gene mutations as genetic modifiers of FTGCT risk. Two genomewide association studies of predominantly sporadic but also familial cases of TGCT have implicated the KIT-ligand, SPRY4, and BAK1 genes as TGCT risk modifiers. All five loci are involved in normal testicular development and/or male infertility. These genetic data provide a novel insight into the genetic basis of FTGCT, and an invaluable guide to future TGCT research.

Figure 1

Factors contributing to the pathogenesis of testicular germ cell tumors. Several genes and genomic regions have been implicated in the pathogenesis of testicular germ cell tumors (TGCTs). Interestingly, all these loci have also been implicated in testicular development. While these variations explain a proportion of the genetic risk, the remaining genetic factors remain undetermined. Epidemiologic data strongly suggest that TGCTs have a significant environmental component. However, these external factors remain poorly defined. Some of the same factors that lead to TGCTs also underlie infertility, providing an explanation for the clinical association between TGCTs and infertility. Possibly, similar relationships are also true for microlithiasis and cryptorchidism. It is conceivable that the familial form of TGCTs is caused by the same factors that lead to sporadic TGCTs; however, we hypothesize that patients with the familial and/or bilateral form of TGCTs have a higher risk score (e.g. a larger number of risk factors).