Abstract
BackgroundTesticular germ cell tumor (TGCT) is the most common malignancy in young men. Familial clustering, epidemiologic evidence of increased risk with family or personal history, and the association of TGCT with genitourinary (GU) tract anomalies have suggested an underlying genetic predisposition. Linkage data have not identified a rare, highly-penetrant, single gene in familial TGCT (FTGCT) cases. Based on its association with congenital GU tract anomalies and suggestions that there is an intrauterine origin to TGCT, we hypothesized the existence of unrecognized dysmorphic features in FTGCT.MethodsWe evaluated 38 FTGCT individuals and 41 first-degree relatives from 22 multiple-case families with detailed dysmorphology examinations, physician-based medical history and physical examination, laboratory testing, and genitourinary imaging studies.ResultsThe prevalence of major abnormalities and minor variants did not significantly differ between either FTGCT individuals or their first-degree relatives when compared with normal population controls, except for tall stature, macrocephaly, flat midface, and retro-/micrognathia. However, these four traits were not manifest as a constellation of features in any one individual or family. We did detect an excess prevalence of the genitourinary anomalies cryptorchidism and congenital inguinal hernia in our population, as previously described in sporadic TGCT, but no congenital renal, retroperitoneal or mediastinal anomalies were detected.ConclusionsOverall, our study did not identify a constellation of dysmorphic features in FTGCT individuals, which is consistent with results of genetic studies suggesting that multiple low-penetrance genes are likely responsible for FTGCT susceptibility.
Highlights
Testicular germ cell tumor (TGCT) is the most common malignancy in young men
We reported no disease-associated germline cytogenetic abnormalities in either the 28 familial TGCT (FTGCT) men we studied by high-resolution chromosome analysis and spectral karyotyping, or 17 previously-reported FTGCT men [12]
A strong correlation between LINE-1 methylation levels among affected father-son pairs suggested possible transgenerational inheritance of an epigenetic event that may be associated with disease risk [24]. These data suggest that a single major locus may not account for the majority of the familial aggregation of TGCT, but rather that multiple low-penetrance susceptibility loci acting in concert may be responsible for the genetic component of TGCT etiology
Summary
Testicular germ cell tumor (TGCT) is the most common malignancy in young men. Familial clustering, epidemiologic evidence of increased risk with family or personal history, and the association of TGCT with genitourinary (GU) tract anomalies have suggested an underlying genetic predisposition. Linkage data have not identified a rare, highly-penetrant, single gene in familial TGCT (FTGCT) cases. The higher relative risk of TGCT among siblings than among fathers/sons suggests both genetic heterogeneity and environmental influences, including possible intrauterine. A strong correlation between LINE-1 methylation levels among affected father-son pairs suggested possible transgenerational inheritance of an epigenetic event that may be associated with disease risk [24]. Overall, these data suggest that a single major locus may not account for the majority of the familial aggregation of TGCT, but rather that multiple low-penetrance susceptibility loci acting in concert may be responsible for the genetic component of TGCT etiology
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