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Testicular germ cell tumor susceptibility associated with the UCK2 locus on chromosome 1q23.

ABSTRACT: Genome-wide association studies (GWASs) have identified multiple common genetic variants associated with an increased risk of testicular germ cell tumors (TGCTs). A previous GWAS reported a possible TGCT susceptibility locus on chromosome 1q23 in the UCK2 gene, but failed to reach genome-wide significance following replication. We interrogated this region by conducting a meta-analysis of two independent GWASs including a total of 940 TGCT cases and 1559 controls for 122 single-nucleotide polymorphisms (SNPs) on chromosome 1q23 and followed up the most significant SNPs in an additional 2202 TGCT cases and 2386 controls from four case-control studies. We observed genome-wide significant associations for several UCK2 markers, the most significant of which was for rs3790665 (PCombined = 6.0 × 10(-9)). Additional support is provided from an independent familial study of TGCT where a significant over-transmission for rs3790665 with TGCT risk was observed (PFBAT = 2.3 × 10(-3)). Here, we provide substantial evidence for the association between UCK2 genetic variation and TGCT risk.

SUBMITTER: Schumacher FR

PROVIDER: S-EPMC3674801 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Testicular germ cell tumor susceptibility associated with the UCK2 locus on chromosome 1q23.

Schumacher Fredrick R FR Wang Zhaoming Z Skotheim Rolf I RI Koster Roelof R Chung Charles C CC Hildebrandt Michelle A T MA Kratz Christian P CP Bakken Anne C AC Bishop D Timothy DT Cook Michael B MB Erickson R Loren RL Fosså Sophie D SD Greene Mark H MH Jacobs Kevin B KB Kanetsky Peter A PA Kolonel Laurence N LN Loud Jennifer T JT Korde Larissa A LA Le Marchand Loic L Lewinger Juan Pablo JP Lothe Ragnhild A RA Pike Malcolm C MC Rahman Nazneen N Rubertone Mark V MV Schwartz Stephen M SM Siegmund Kimberly D KD Skinner Eila C EC Turnbull Clare C Van Den Berg David J DJ Wu Xifeng X Yeager Meredith M Nathanson Katherine L KL Chanock Stephen J SJ Cortessis Victoria K VK McGlynn Katherine A KA

Human molecular genetics 20130305 13

Genome-wide association studies (GWASs) have identified multiple common genetic variants associated with an increased risk of testicular germ cell tumors (TGCTs). A previous GWAS reported a possible TGCT susceptibility locus on chromosome 1q23 in the UCK2 gene, but failed to reach genome-wide significance following replication. We interrogated this region by conducting a meta-analysis of two independent GWASs including a total of 940 TGCT cases and 1559 controls for 122 single-nucleotide polymor ...[more]

PMID: 23462292

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Project description:BackgroundComplex genetic factors underlie testicular germ cell tumor (TGCT) development. One experimental approach to dissect the genetics of TGCT predisposition is to use chromosome substitution strains, such as the 129.MOLF-Chr 19 (M19). M19 carries chromosome (Chr) 19 from the MOLF whereas all other chromosomes are from the 129 strain. 71% of M19 males develop TGCTs in contrast to 5% in 129 strain. To identify and map tumor loci from M19 we generated congenic strains harboring MOLF chromosome 19 segments on 129 strain background and monitored their TGCT incidence.ResultsWe found 3 congenic strains that each harbored tumor promoting loci that had high (14%-32%) whereas 2 other congenics had low (4%) TGCT incidences. To determine how multiple loci influence TGCT development, we created double and triple congenic strains. We found additive interactions were predominant when 2 loci were combined in double congenic strains. Surprisingly, we found an example where 2 loci, both which do not contribute significantly to TGCT, when combined in a double congenic strain resulted in greater than expected TGCT incidence (positive interaction). In an opposite example, when 2 loci with high TGCT incidences were combined, males of the double congenic showed lower than expected TGCT incidence (negative interaction). For the triple congenic strain, depending on the analysis, the overall TGCT incidence could be additive or could also be due to a positive interaction of one region with others. Additionally, we identified loci that promote bilateral tumors or testicular abnormalities.ConclusionsThe congenic strains each with their characteristic TGCT incidences, laterality of tumors and incidence of testicular abnormalities, are useful for identification of TGCT susceptibility modifier genes that map to Chr 19 and also for studies on the genetic and environmental causes of TGCT development. TGCTs are a consequence of aberrant germ cell and testis development. By defining predisposing loci and some of the locus interactions from M19, this study further advances our understanding of the complex genetics of TGCTs, which is the most common cancer in young human males.

Dataset Information

Testicular germ cell tumor susceptibility associated with the UCK2 locus on chromosome 1q23.

Publications

Testicular germ cell tumor susceptibility associated with the UCK2 locus on chromosome 1q23.

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