Selinski, Silvia

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EXCLI Journal 2013;12:1017-1019 – ISSN 1611-2156 Received: December 04, 2013, accepted: December 05, 2013, published: December 05, 2013  1017 Editorial: HIGHLIGHT REPORT: FUNCTIONAL CONSEQUENCES OF URINARY BLADDER CANCER RISK VARIANTS  Silvia Selinski  Leibniz Research Centre for Working Environment and Human Factors, Dortmund/Germany Selinski@ifado.de    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 aro-matic amines and cigarette smoking (Golka et al., 2012; Ovsiannikov et al., 2012; Selinski et al., 2013; Kempkes et al., 1996). Recently, genome-wide association studies have successfully identified several urinary bladder cancer susceptibility loci (review: Dudek et al., 2013; Golka et al., 2011; Selinski, 2012; Bolt, 2013a, b). Currently confirmed genetic variants include rs9642880 (MYC, Kiemeney et al., 2008; Golka et al., 2009), rs710521 (TP63, Kiemeney et al., 2008; Lehmann et al., 2010), rs401681 and rs2736098 (CLPTM1L, TERT, Rafnar et al., 2009), rs2294008 and rs2978974 (PSCA, Wu et al., 2009; Fu et al., 2012), rs798766 (TACC3, FGFR3, Kiemeney et al., 2010), rs11892031 (UGT1A, Rothman et al., 2010; Selinski et al., 2012), rs17863783 (UGT1A6, Tang et al., 2012), rs1495741 (NAT2, Rothman et al., 2010; Garcia-Closas et al., 2011; Selinski et al., 2011), rs8102137 (CCNE1, Rothman et al., 2010), rs1014971 (CBX6, Rothman et al., 2010) and rs17674580 and rs1058396 (SLC14A1, Rafnar et al., 2011). Moreover, it has been shown that several high risk alleles of sin-gle nucleotide polymorphisms can interact leading to enhanced odds ratios (Schwender et al., 2012). 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). Similarly, rs1014971 on 22q13.1 is located 25 kb and 64kb from APOBEC3A and CBX6, respectively (Rothman et al., 2010). Considering these relatively large distances between both SNPs and the clos-est exons it seems unlikely that an influence can be explained by linkage disequilibrium. Recently, Dudek and colleagues have ad-dressed the open question of the functional consequences of urinary bladder suscepti-bility loci (Dudek et al., 2013). At least two risk variants, located in PSCA and UGT1A, were confirmed to have functional conse-quences.  PSCA (prostate stem cell antigen) is involved in the regulation of stem cell proliferation. Rs2294008 is located in the first exon of PSCA (review: Dudek et al., 2013). It changes a nucleotide in the initiation region, creates a new ATG for translation initiation leading to a PSCA protein which is nine amino acids longer (Dudek et al., 2013). Rs294008 was found to be strongly associated with PSCA protein levels in urinary bladder tumors. Moreover, a second variant, rs2978974, was also identified in exon 1 of PSCA and was found to be associated with urinary bladder cancer risk (Fu et al., 2012; review: Dudek et al., 2013).  UDP-glucuronosyltransferase (UGT) is a phase II metabolizing enzyme in-volved in detoxification of numerous EXCLI Journal 2013;12:1017-1019 – ISSN 1611-2156 Received: December 04, 2013, accepted: December 05, 2013, published: December 05, 2013  1018 carcinogens (Burkhardt et al., 2012; Hanioka et al., 2011; Luo et al., 2012; Godoy et al., 2013). One bladder cancer susceptibility locus is located in intron 1 of UGT, containing rs11892031 (Roth-man et al., 2010; Dudek et al., 2013). Follow-up studies identified the causa-tive variant rs17863783 (Tang et al. 2012). Rs17863783 does not alter the amino acid sequence of UGT1A. How-ever, a possible explanation is that rs17863783 modifies the expression of UGT1A by influencing the exonic splic-ing enhancer, a DNA sequence motif essential for the identification of splice sites (Dudek et al., 2013).  The current review article of Dudek et al. (2013) describes in a comprehensive way the current concepts by which mecha-nisms the recently identified bladder cancer risk loci may contribute to carcinogenesis.   REFERENCES Bolt HM. Human bladder cancer risk calculation based on genome-wide analysis of genetic variants. Arch Toxicol 2013a;87:397-9.  Bolt HM. Relevance of genetic disposition versus environmental exposure for cancer risk: an old con-troversy revisited with novel methods. EXCLI J 2013b;79:196-200.  Burkhardt B, Jung SA, Pfeiffer E, Weiss C, Metzler M. Mouse hepatoma cell lines differing in aryl hy-drocarbon receptor-mediated signaling have differ-ent activities for glucuronidation. Arch Toxicol 2012;86:643-9.  Dudek AM, Grotenhuis AJ, Vermeulen SH, Kie-meney LA, Verhaegh GW. Urinary bladder cancer susceptibility markers. What do we know about functional mechanisms? Int J Mol Sci 2013;14: 12346-66.  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.  García-Closas M, Hein DW, Silverman D, Malats N, Yeager M, Jacobs K et al. A single nucleotide poly-morphism tags variation in the arylamine N-acetyltransferase 2 phenotype in populations of Eu-ropean background. Pharmacogenet Genomics 2011; 21:231-6.  Godoy P, Hewitt NJ, Albrecht U, Andersen ME, Ansari N, Bhattacharya S et al. 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Hanioka N, Oka H, Nagaoka K, Ikushiro S, Narima-tsu S: Effect of UDP-glucuronosyltransferase 2B15 polymorphism on bisphenol A glucuronidation. Arch Toxicol 2011;85:1373-81.  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.  Kiemeney LA, Thorlacius S, Sulem P, Geller F, Aben KK, Stacey SN et al. Sequence variant on 8q24 confers susceptibility to urinary bladder can-cer. Nat Genet 2008;40:1307-12.   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.   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.  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Rs11892031[A] on chromosome 2q37 in an intronic region of the UGT1A locus is associated with uri-nary bladder cancer risk. Arch Toxicol 2012;86: 1369-78.  Selinski S, Blaszkewicz M, Agundez JA, Martinez C, Garcia-Martin E, Hengstler JG et al. Clarifying haplotype ambiguity of NAT2 in multi-national co-horts. Front Biosci (Schol Ed) 2013;5:672-84.  Tang W, Fu YP, Figueroa JD, Malats N, Garcia-Closas M, Chatterjee N et al. Mapping of the UGT1A locus identifies an uncommon coding vari-ant that affects mRNA expression and protects from bladder cancer. Hum Mol Genet 2012;21:1918-30.  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. 

Functional consequences of urinary bladder cancer risk variants

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Functional consequences of urinary bladder cancer risk variants

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