Revision: Endocrine-Related Cancer Familial Testicular Germ Cell Tumors in Adults: 2010 Summary of Genetic Risk Factors and Clinical Phenotype

Familial aggregations of testicular germ cell tumor (FTGCT) have been well-described, suggesting the existence of an 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 4-6 fold and 8-10 fold 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 affecteds is two. Age-at-diagnosis is 2-3 years younger for familial versus sporadic cases. The ratio of familial seminoma to non-seminoma is 1.0. Familial TGCT 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 chromosome Y 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 5 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. BACKGROUND Page 2 of 29