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Are Genetic Variants That Influence Testicular Germ Cell Cancer Risk Also Involved in Hypospadias and Undescended Testes?: A Case-Parent Study
Ruthie Su, MD1, Steve Schwartz, PhD, MPH2, Margarett Shnorhavorian, MD, MPH1.
1Seattle Children's Hospital, Seattle, WA, USA, 2Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA.

Background: The testis dysgenesis syndrome (TDS) theory proposes that hypospadias, undescended testis (UDT), and testis germ cell tumors (TGCT) have a common etiology. Genetic risk factors for TGCT have recently been identified by genome wide association studies (GWAS). The aim of this study was to investigate whether genetic variants associated with TGCT are also associated with hypospadias and UDT. For the first time, the role of maternal genotype effects of TGCT risk variants on the risk of hypospadias and UDT was also explored.
Methods:We conducted a case-parent study of boys diagnosed with hypospadias (n=50) or UDT (n=127) during 2005-2012 at our institution. DNA from boys and their parents was obtained using Oragene kits (DNA Genotek Inc). DNA was genotyped using Fluidigm arrays for single nucleotide polymorphisms (SNPs) previously shown to be associated with TGCT in GWAS: BAK1 (rs210138), DMRT1 (rs7040024, rs755383), TERT-CLPTM1L (rs2736100), ATF71P (rs2900333), UCK2 (rs3790665), KITLG (rs4474514), RFWD3 (rs4888262), SPRY4 (rs6897876), PPM1E (rs7221274), TEX14 (rs9905704), MAD1L1 (rs12699477), and HPGDS (rs17021463). Log-linear regression models were used to analyze case parent triads (36 hypospadias, 93 UDT) and dyads (14 hypospadia, 34 UDT) to independently assess the relative risk (RR) associated with the mother's or son's carrying one or two copies of each SNP’s risk allele.
Results: Offspring carriage of the UCK2 rs3790665 A allele was significantly associated with UDT (p=0.009); UDT risk increased with the number of A alleles (heterozygote RR=1.51, 95%Confidence Interval (CI) 0.81-2.83; homozygote RR=2.58, 95%CI 0.58-11.59). Maternal carriage of the DMRT1 rs755383 T allele was significantly (p=0.02) associated with UDT (heterozygote RR=1.2, 95%CI 0.55-2.68; homozygote RR=7.37, 95%CI 1.6-34.10). When only UDT patients with White, Non-Hispanics parents were analyzed (62 triads), maternal carriage of the DMRT1 T allele was not significantly associated with UDT (p=0.156) but a similar trend in RRs was observed (heterozygote RR=1.05, 95% CI 0.47-2.32; homozygote RR 4.39, 95%CI 0.95-20.29). No SNP included in this study was observed to be significantly associated with the hypospadias.
Conclusions: Child and maternal genotype variants of UCK2 and DMRT1 SNPs, respectively, appear to be genetic risk factors for UDT. Our results provide support for the hypothesis that TGCT and UDT share some etiologic factors. Further study of genetic variants common to UDT and TGCT is warranted with potential impact on future screening strategies.


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