Editorial

Highlight report: Functional consequences of urinary bladder cancer risk variants

Silvia Selinski1[*]

1Leibniz Research Centre for Working Environment and Human Factors, Dortmund/Germany

EXCLI J 2013;12:Doc1017

 



About 180,000 new cases of urinary bladder cancer are diagnosed each year in the European Union. The most relevant risk factors are occupational exposure to aromatic amines and cigarette smoking (Golka et al., 2012[8]; Ovsiannikov et al., 2012[17]; Selinski et al., 2013[23]; Kempkes et al., 1996[12]). Recently, genome-wide association studies have successfully identified several urinary bladder cancer susceptibility loci (review: Dudek et al., 2013[4]; Golka et al., 2011[10]; Selinski, 2012[22]; Bolt, 2013[1][2]). Currently confirmed genetic variants include rs9642880 (MYC, Kiemeney et al., 2008[14]; Golka et al., 2009[9]), rs710521 (TP63, Kiemeney et al., 2008[14]; Lehmann et al., 2010[15]), rs401681 and rs2736098 (CLPTM1L, TERT, Rafnar et al., 2009[18]), rs2294008 and rs2978974 (PSCA, Wu et al., 2009[27]; Fu et al., 2012[5]), rs798766 (TACC3, FGFR3, Kiemeney et al., 2010[13]), rs11892031 (UGT1A, Rothman et al., 2010[20]; Selinski et al., 2012[25]), rs17863783 (UGT1A6, Tang et al., 2012[26]), rs1495741 (NAT2, Rothman et al., 2010[20]; Garcia-Closas et al., 2011[6]; Selinski et al., 2011[24]), rs8102137 (CCNE1, Rothman et al., 2010[20]), rs1014971 (CBX6, Rothman et al., 2010[20]) and rs17674580 and rs1058396 (SLC14A1, Rafnar et al., 2011[19]). Moreover, it has been shown that several high risk alleles of single nucleotide polymorphisms can interact leading to enhanced odds ratios (Schwender et al., 2012[21]). However, relatively little is known about the functional consequences of the novel bladder cancer susceptibility SNPs. Many of them are located in non-coding regions. An example is rs9642880 on chromosome 8q24 that is approximately 30kb upstream of MYC (Kiemeney et al., 2008[14]). Similarly, rs1014971 on 22q13.1 is located 25 kb and 64kb from APOBEC3A and CBX6, respectively (Rothman et al., 2010[20]). Considering these relatively large distances between both SNPs and the closest exons it seems unlikely that an influence can be explained by linkage disequilibrium. Recently, Dudek and colleagues have addressed the open question of the functional consequences of urinary bladder susceptibility loci (Dudek et al., 2013[4]). At least two risk variants, located in PSCA and UGT1A, were confirmed to have functional consequences.

The current review article of Dudek et al. (2013[4]) describes in a comprehensive way the current concepts by which mechanisms the recently identified bladder cancer risk loci may contribute to carcinogenesis.

 

References

1. Bolt HM. Human bladder cancer risk calculation based on genome-wide analysis of genetic variants. Arch Toxicol. 2013;87:397-9.
2. Bolt HM. Relevance of genetic disposition versus environmental exposure for cancer risk: an old controversy revisited with novel methods. EXCLI J. 2013;79:196-200.
3. Burkhardt B, Jung SA, Pfeiffer E, Weiss C, Metzler M. Mouse hepatoma cell lines differing in aryl hydrocarbon receptor-mediated signaling have different activities for glucuronidation. Arch Toxicol. 2012;86:643-9.
4. Dudek AM, Grotenhuis AJ, Vermeulen SH, Kiemeney LA, Verhaegh GW. Urinary bladder cancer susceptibility markers. What do we know about functional mechanisms? Int J Mol Sci. 2013;14:12346-66.
5. Fu YP, Kohaar I, Rothman N, Earl J, Figueroa JD, Ye Y, et al. Common genetic variants in the PSCA gene influence gene expression and bladder cancer risk. Proc Natl Acad Sci U S A. 2012;109:4974-9.
6. García-Closas M, Hein DW, Silverman D, Malats N, Yeager M, Jacobs K, et al. A single nucleotide polymorphism tags variation in the arylamine N-acetyltransferase 2 phenotype in populations of European background. Pharmacogenet Genomics. 2011;21:231-6.
7. Godoy P, Hewitt NJ, Albrecht U, Andersen ME, Ansari N, Bhattacharya S, et al. Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME. Arch Toxicol. 2013;87:1315-530.
8. Golka K, Abreu-Villaca Y, Anbari Attar R, Angeli-Greaves M, Aslam M, Basaran N, et al. Bladder cancer documentation of causes: multilingual questionnaire, 'bladder cancer doc'. Front Biosci (Elite Ed). 2012;4:2809-22.
9. Golka K, Hermes M, Selinski S, Blaszkewicz M, Bolt HM, Roth G, et al. Susceptibility to urinary bladder cancer: relevance of rs9642880[T], GSTM1 0/0 and occupational exposure. Pharmacogenet Genomics. 2009;19:903-6.
10. Golka K, Selinski S, Lehmann ML, Blaszkewicz M, Marchan R, Ickstadt K, et al. Genetic variants in urinary bladder cancer: collective power of the "wimp SNPs". Arch Toxicol. 2011;85:539-54.
11. Hanioka N, Oka H, Nagaoka K, Ikushiro S, Narimatsu S. Effect of UDP-glucuronosyltransferase 2B15 polymorphism on bisphenol A glucuronidation. Arch Toxicol. 2011;85:1373-81.
12. Kempkes M, Golka K, Reich S, Reckwitz T, Bolt HM. Glutathione S-transferase GSTM1 and GSTT1 null genotypes as potential risk factors for urothelial cancer of the bladder. Arch Toxicol. 1996;71:123-6.
13. Kiemeney LA, Sulem P, Besenbacher S, Vermeulen SH, Sigurdsson A, Thorleifsson G, et al. A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer. Nat Genet. 2010;42:415-9.
14. Kiemeney LA, Thorlacius S, Sulem P, Geller F, Aben KK, Stacey SN, et al. Sequence variant on 8q24 confers susceptibility to urinary bladder cancer. Nat Genet. 2008;40:1307-12.
15. Lehmann ML, Selinski S, Blaszkewicz M, Orlich M, Ovsiannikov D, Moormann O, et al. Rs710521[A] on chromosome 3q28 close to TP63 is associated with increased urinary bladder cancer risk. Arch Toxicol. 2010;84:967-78.
16. Luo CF, Cai B, Hou N, Yuan M, Liu SM, Ji H, et al. UDP-glucuronosyltransferase 1A1 is the principal enzyme responsible for puerarin metabolism in human liver microsomes. Arch Toxicol. 2012;86:1681-90. Erratum in: Arch Toxicol. 2012;86:1691.
17. Ovsiannikov D, Selinski S, Lehmann ML, Blaszkewicz M, Moormann O, Haenel MW, et al. Polymorphic enzymes, urinary bladder cancer risk, and structural change in the local industry. J Toxicol Environ Health A. 2012;75:557-65.
18. Rafnar T, Sulem P, Stacey SN, Geller F, Gudmundsson J, Sigurdsson A, et al. Sequence variants at the TERT-CLPTM1L locus associate with many cancer types. Nat Genet. 2009;41:221-7.
19. Rafnar T, Vermeulen SH, Sulem P, Thorleifsson G, Aben KK, Witjes JA, et al. European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene. Hum Mol Genet. 2011;20:4268-81.
20. Rothman N, Garcia-Closas M, Chatterjee N, Malats N, Wu X, Figueroa JD, et al. A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci. Nat Genet. 2010;42:978-84.
21. Schwender H, Selinski S, Blaszkewicz M, Marchan R, Ickstadt K, Golka K, et al. Distinct SNP combinations confer susceptibility to urinary bladder cancer in smokers and non-smokers. PLoS One. 2012;7:e51880.
22. Selinski S. Genetic variants confer susceptibility to urinary bladder cancer: an updated list of confirmed polymorphisms. EXCLI J. 2012;11:743-7.
23. Selinski S, Blaszkewicz M, Agundez JA, Martinez C, Garcia-Martin E, Hengstler JG, et al. Clarifying haplotype ambiguity of NAT2 in multi-national cohorts. Front Biosci (Schol Ed). 2013;5:672-84.
24. Selinski S, Blaszkewicz M, Lehmann ML, Ovsiannikov D, Moormann O, Guballa C, et al. Genotyping NAT2 with only two SNPs (rs1041983 and rs1801280) outperforms the tagging SNP rs1495741 and is equivalent to the conventional 7-SNP NAT2 genotype. Pharmacogenet Genomics. 2011;21:673-8.
25. Selinski S, Lehmann ML, Blaszkewicz M, Ovsiannikov D, Moormann O, Guballa C, et al. Rs11892031[A] on chromosome 2q37 in an intronic region of the UGT1A locus is associated with urinary bladder cancer risk. Arch Toxicol. 2012;86:1369-78.
26. Tang W, Fu YP, Figueroa JD, Malats N, Garcia-Closas M, Chatterjee N, et al. Mapping of the UGT1A locus identifies an uncommon coding variant that affects mRNA expression and protects from bladder cancer. Hum Mol Genet. 2012;21:1918-30.
27. Wu X, Ye Y, Kiemeney LA, Sulem P, Rafnar T, Matullo G, et al. Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer. Nat Genet. 2009;41:991-5.
 
 
 

[*] Corresponding Author:

Silvia Selinski, Leibniz Research Centre for Working Environment and Human Factors, Dortmund/Germany, eMail: Selinski@ifado.de