Recent advances in genetic predisposition to primary testicular tumors

There have been considerable recent advances in our understanding of the genetic predisposition to testicular tumors. In germ cell tumors derived from germ cell neoplasia in situ, which comprise the majority (approximately 95%) of primary testicular neoplasms, research has firmly established a polygenic model of inheritance where risk is not conferred by single high-penetrance genes but rather by the cumulative impact of numerous common, low-penetrance risk alleles. These susceptibility loci have been identified primarily through genome wide association studies and involve genes in pathways including germ cell development, telomere maintenance, and DNA damage repair, among other pathways. A more recent significant advancement is the association of GCTs with pathogenic CHEK2 variants; this represents the first moderate penetrance predisposition gene identified for germ cell tumors. In germ cell neoplasia in situ-independent neoplasms, there is a growing number of recognized associations of sex cord stromal tumors with well-defined monogenic hereditary cancer syndromes including Carney Complex (PRKAR1A), Peutz-Jeghers Syndrome (STK11), and HLRCC (FH). Further associations with Familial Adenomatous Polyposis Syndrome (APC) and DICER1-Syndrome have also recently been described but require further confirmation. This review discusses the genetic predispositions across testicular cancer, with an emphasis on areas for future research.