Abstract
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.
Highlights
Only 7920 incident cases of testicular germ cell tumor (TGCT) are expected in the United States this year [1], TGCT has substantial public health impact as the most common cancer affecting men aged 20–35 years
Eighty-four non-TGCT cancers were observed among first-degree relatives of the nearest TGCT case during the study period (Norway = 42; United States = 42)
In this quantitative study of cancer risk within multiplecase TGCT families, we found no excess risk of nonTGCT cancers at all sites combined among first-degree relatives of TGCT cases
Summary
Only 7920 incident cases of testicular germ cell tumor (TGCT) are expected in the United States this year [1], TGCT has substantial public health impact as the most common cancer affecting men aged 20–35 years. Several TGCT risk factors have been confirmed, including family history [2], previous contralateral testicular cancer [3], cryptorchidism [4], infertility [5], testicular microlithiasis [6], testicular developmental anomalies and atrophy [7, 8], adult height [9], and in utero exposure to diethylstilbestrol [10]. Apart from the contribution of these factors to TGCT development, this disease is notable for its striking heritability. Compared with most familial relative risks of 1.5- to 2.5-fold for first-degree relatives of common adult cancers, the risks to an individual whose brother or father has TGCT have been estimated as eight- to 10-fold and four- to sixfold,.
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