Testicular Germ Cell Tumor Susceptibility Associated with the UCK2 Locus on Chromosome 1q23

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.

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References

Cook M, Akre O, Forman D, Madigan M, Richiardi L, McGlynn K . A systematic review and meta-analysis of perinatal variables in relation to the risk of testicular cancer--experiences of the son. Int J Epidemiol. 2010; 39(6):1605-18. PMC: 2992627. DOI: 10.1093/ije/dyq120. View

Meike S, Yamamori T, Yasui H, Eitaki M, Matsuda A, Morimatsu M . A nucleoside anticancer drug, 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)cytosine (TAS106), sensitizes cells to radiation by suppressing BRCA2 expression. Mol Cancer. 2011; 10:92. PMC: 3161955. DOI: 10.1186/1476-4598-10-92. View

Ozaki K, Kuroki T, Hayashi S, Nakamura Y . Isolation of three testis-specific genes (TSA303, TSA806, TSA903) by a differential mRNA display method. Genomics. 1996; 36(2):316-9. DOI: 10.1006/geno.1996.0467. View

Shimamoto Y, Koizumi K, Okabe H, Kazuno H, Murakami Y, Nakagawa F . Sensitivity of human cancer cells to the new anticancer ribo-nucleoside TAS-106 is correlated with expression of uridine-cytidine kinase 2. Jpn J Cancer Res. 2002; 93(7):825-33. PMC: 5927072. DOI: 10.1111/j.1349-7006.2002.tb01325.x. View

Turnbull C, Rapley E, Seal S, Pernet D, Renwick A, Hughes D . Variants near DMRT1, TERT and ATF7IP are associated with testicular germ cell cancer. Nat Genet. 2010; 42(7):604-7. PMC: 3773909. DOI: 10.1038/ng.607. View

Starr J, Chen C, Doody D, Hsu L, Ricks S, Weiss N . Risk of testicular germ cell cancer in relation to variation in maternal and offspring cytochrome p450 genes involved in catechol estrogen metabolism. Cancer Epidemiol Biomarkers Prev. 2005; 14(9):2183-90. DOI: 10.1158/1055-9965.EPI-04-0749. View

Gerstein M, Kundaje A, Hariharan M, Landt S, Yan K, Cheng C . Architecture of the human regulatory network derived from ENCODE data. Nature. 2012; 489(7414):91-100. PMC: 4154057. DOI: 10.1038/nature11245. View

Hemminki K, Li X . Familial risk in testicular cancer as a clue to a heritable and environmental aetiology. Br J Cancer. 2004; 90(9):1765-70. PMC: 2410275. DOI: 10.1038/sj.bjc.6601714. View

Forman D, Oliver R, Brett A, Marsh S, Moses J, Bodmer J . Familial testicular cancer: a report of the UK family register, estimation of risk and an HLA class 1 sib-pair analysis. Br J Cancer. 1992; 65(2):255-62. PMC: 1977724. DOI: 10.1038/bjc.1992.51. View

10.

Kristiansen W, Andreassen K, Karlsson R, Aschim E, Bremnes R, Dahl O . Gene variations in sex hormone pathways and the risk of testicular germ cell tumour: a case-parent triad study in a Norwegian-Swedish population. Hum Reprod. 2012; 27(5):1525-35. DOI: 10.1093/humrep/des075. View

11.

Chia V, Quraishi S, Devesa S, Purdue M, Cook M, McGlynn K . International trends in the incidence of testicular cancer, 1973-2002. Cancer Epidemiol Biomarkers Prev. 2010; 19(5):1151-9. PMC: 2867073. DOI: 10.1158/1055-9965.EPI-10-0031. View

12.

Van Rompay A, Norda A, Linden K, Johansson M, Karlsson A . Phosphorylation of uridine and cytidine nucleoside analogs by two human uridine-cytidine kinases. Mol Pharmacol. 2001; 59(5):1181-6. DOI: 10.1124/mol.59.5.1181. View

13.

Horvath S, Xu X, Laird N . The family based association test method: strategies for studying general genotype--phenotype associations. Eur J Hum Genet. 2001; 9(4):301-6. DOI: 10.1038/sj.ejhg.5200625. View

14.

Czene K, Lichtenstein P, Hemminki K . Environmental and heritable causes of cancer among 9.6 million individuals in the Swedish Family-Cancer Database. Int J Cancer. 2002; 99(2):260-6. DOI: 10.1002/ijc.10332. View

15.

Horvath A, Korde L, Greene M, Libe R, Osorio P, Rueda Faucz F . Functional phosphodiesterase 11A mutations may modify the risk of familial and bilateral testicular germ cell tumors. Cancer Res. 2009; 69(13):5301-6. PMC: 2734464. DOI: 10.1158/0008-5472.CAN-09-0884. View

16.

Ferlin A, Ganz F, Pengo M, Selice R, Frigo A, Foresta C . Association of testicular germ cell tumor with polymorphisms in estrogen receptor and steroid metabolism genes. Endocr Relat Cancer. 2009; 17(1):17-25. DOI: 10.1677/ERC-09-0176. View

17.

Ward L, Kellis M . HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 2011; 40(Database issue):D930-4. PMC: 3245002. DOI: 10.1093/nar/gkr917. View

18.

Dieckmann K, Pichlmeier U . The prevalence of familial testicular cancer: an analysis of two patient populations and a review of the literature. Cancer. 1997; 80(10):1954-60. View

19.

Kratz C, Greene M, Bratslavsky G, Shi J . A stratified genetic risk assessment for testicular cancer. Int J Androl. 2011; 34(4 Pt 2):e98-102. PMC: 3145032. DOI: 10.1111/j.1365-2605.2011.01156.x. View

20.

Heimdal K, Olsson H, Tretli S, Flodgren P, Borresen A, Fossa S . Familial testicular cancer in Norway and southern Sweden. Br J Cancer. 1996; 73(7):964-9. PMC: 2074255. DOI: 10.1038/bjc.1996.173. View