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.
Testicular germ cell tumors (TGCT) exhibit striking familial aggregation that remains incompletely explained. To improve the phenotypic definition of familial TGCT (FTGCT), we studied an ...international cohort of multiple‐case TGCT families to determine whether first‐degree relatives of FTGCT cases are at increased risk of other types of cancer. We identified 1041 first‐degree relatives of TGCT cases in 66 multiple‐case TGCT families from Norway and 64 from the United States (combined follow‐up of 31,556 person‐years). We collected data on all cancers (except nonmelanoma skin cancers) reported by the family informant in these relatives, and we attempted to verify all reported cancer diagnoses through medical or cancer registry records. We calculated observed‐to‐expected (O/E) standardized incidence ratios, together with 95% confidence intervals (CI), for invasive cancers other than TGCT. We found no increase in risk of cancer overall (Norway O/E = 0.8; 95% CI: 0.6–1.1 and United States O/E = 0.9; 95% CI: 0.7–1.3). Site‐specific analyses pooled across the two countries revealed a leukemia excess (O/E = 6.5; 95% CI: 3.0–12.3), deficit of female breast cancer (O/E = 0.0; 95% CI: 0.0–0.6) and increased risk of soft tissue sarcoma (O/E = 7.2; 95% CI: 2.0–18.4); in all instances, these results were based on small case numbers and statistically significant only in Norway. While limited by sample size and potential issues relating to completeness of cancer reporting, this study in multiple‐case TGCT families does not support the hypothesis that cancers other than testis cancer contribute to the FTGCT phenotype.
We identified 1041 first‐degree relatives of testicular germ cell tumor (TGCT) case in 66 multiple‐case TGCT families from Norway and 64 families from the United States (combined follow‐up of 31,556 person‐years. We calculated observed‐to‐expected standardized incidence rations, together with 95% confidence intervals, for invasive cancers other than TGCT occurring in these individuals. We found no risk of cancer overall, suggesting that familial TGCT may be a site‐specific syndrome.
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