Selinski, Silvia

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EXCLI Journal 2012;11:743-747 – ISSN 1611-2156 Received: November 07, 2012, published: November 14, 2012  743 Editorial: GENETIC VARIANTS CONFER SUSCEPTIBILITY TO URINARY BLADDER CANCER: AN UPDATED LIST OF CONFIRMED  POLYMORPHISMS  Silvia Selinski  Leibniz Institut für Arbeitsforschung an der TU Dortmund, Leibniz Research Centre for Working Environment and Human Factors (IfADo), Ardeystrasse 67, 44139 Dortmund,  Germany selinski@ifado.de   Urinary bladder cancer is the 7th most common cancer in Western Europe (Ferlay et al., 2012). The most relevant risk factors are occupational exposure to aromatic amines and poly-cyclic aromatic hydrocarbons as well as cigarette smoking (Golka et al., 2012, 2009, 2004; Schwender et al., 2012). Moreover, polymorphisms of phase II metabolizing enzymes are well-known since decades to increase bladder cancer risk, in particular, the deletion variant of the phase II metabolizing enzyme glutathione-S-transferase M1 (GSTM1) (Ovsiannikov et al., 2012; Golka et al., 2009, 1997; Arand et al., 1996) and polymorphisms in the N-acetyltranferase 2 (NAT2) gene leading to a reduced acetylation capacity (Selinski et al., 2011; Moore et al., 2011; Golka et al., 2002, 1996), and currently their influence on prognosis is investigated (Roth et al., 2012; Nørskov et al., 2011). Recently, genome-wide association studies (GWAS) have identified several novel nucleotide polymorphisms (SNPs) as associat-ed with urinary bladder cancer (UBC) risk and most of them could be confirmed in independ-ent follow-up case-control series (review: Golka et al., 2011; Table 1). So far SNPs at ten chromosomal locations, besides GSTM1, have been identified. The functions of the closest genes are related to maintenance of DNA integrity, apoptosis and cell cycle control as well as detoxification of carcinogens. Considering the large size of the case-control series with more than 4,500 cases and 45,000 controls (Rafnar et al., 2011; Kiemeney et al., 2010; Rothman et al., 2010), the high density of polymorphisms on SNP chips as well as the accuracy of SNP imputation algorithms it may be regarded as likely that the most influential SNPs have now been discovered. However, one open question remains: to date it is completely unknown, if the novel SNPs interact. If so, will they result in less than additive, additive or even over addi-tive risks? How high is the population attributable risk of the combined influence of all poly-morphisms? And how important is the combined genetic risk compared to the risk attributable to cigarette smoking and occupational exposure to bladder carcinogens? Considering the re-cent progress in genome-wide association studies it can be expected that answers to these questions will soon be available.   First analyses beyond the standard single SNP analyses in case-control designs yield promis-ing results (Binder et al., 2012; Menashe et al., 2012; Schwender et al., 2012).   EXCLI Journal 2012;11:743-747 – ISSN 1611-2156 Received: November 07, 2012, published: November 14, 2012  744 Table 1: Currently confirmed genetic variants that are associated with bladder cancer risk. Polymor-phisms and related genes are printed bold, risk alleles are given in brackets. Key message Reference  Rs9642880[T] near proto-oncogene MYC (v-myc myelocytomatosis viral oncogene homolog (avian) was associated with UBC in a GWAS (OR=1.22). Kiemeney et al., 2008 The effect of rs9642880[T] was less pronounced in cases with sus-pected exposure to bladder carcinogens (OR=1.04 and 1.11 exposed study groups; OR=1.36 non-exposed) for which GSTM1 null is the more important genetic risk factor (OR=2.43 and 1.38 exposed; OR=1.22 non-exposed). Golka et al., 2009 Rs710521[A] near the TP63 (tumor protein 63) gene, that encodes for a member of the p53 family of transcription factors, was associat-ed with UBC in a GWAS (OR=1.19). Kiemeney et al., 2008 The effect of rs710521[A] on UBC risk (OR=1.16) did not depend on exposure to bladder carcinogens via tobacco smoke or occupation.  Lehmann et al., 2010 Rs401681[C] in an intron of CLPTM1L (cisplatin resistance related protein CRR9p) and the nearby synonymous rs2736098[A] in the 2nd exon of TERT (telomerase reverse transcription) were both associat-ed with UBC in a GWAS (OR=1.12; OR=1.16). The CLPTM1L gene associated with cisplatin-induced apoptosis and the nearby TERT that is involved in telomere maintenance and thus in aging are located at a potential cancer susceptibility locus at 5p15.33. Rafnar et al., 2009 Rs2294008[T] alters the start codon of PSCA (prostate stem cell an-tigen) leading to a reduced promoter activity in vitro and was associ-ated with UBC in a GWAS (OR=1.15). PSCA is over-expressed in prostate and bladder tumors. Wu et al., 2009 Rs2978974[A] in an alternative untranslated 1st exon of PSCA was associated with UBC in a fine-mapping study (OR=1.11) and interact-ed with rs2294008 10 kb upstream rs2978974.  Fu et al., 2012 Rs798766[T] in an intron of TACC3 (transforming, acidic coiled-coil containing protein 3), 70 kb of FGFR3 (fibroblast growth factor recep-tor 3) was associated with UBC in a GWAS (OR=1.24).  Kiemeney et al., 2010 Rs11892031[C] in an intronic region in the UGT1A (UDP glucu-ronosyltransferase 1 family, polypeptide A complex locus) cluster was associated with UBC in a GWAS (OR=0.84) showing a protective ef-fect of the minor allele [C]. UGT1A proteins are involved in the me-tabolisms of bladder carcinogens via glucuronidation. Rothman et al., 2010 Rs11892031[C] showed a more pronounced protective effect in per-sons with occupational exposure to polycyclic aromatic hydrocarbons and aromatic amines (OR=0.68 exposed; OR=0.83 all combined).  Selinski et al., 2012 Rs17863783[T] a synonymous rare (2 %) SNP in a UGT1A6 exon was shown to increase UGT1A6.1 mRNA expression in vitro and was associated with UBC in a fine-mapping study (OR=0.55). Rs17863783 explained most of the effect of rs11892031. Tang et al., 2012 Rs1495741[A] a tagSNP for NAT2 (N-acetyltransferase 2) activity, 14 kb 3' of NAT2, was associated with UBC in a GWAS (ORA/A=1.15). Polymorphisms of NAT2 lead to a reduced acetylation of drugs and xenobiotics (“slow” and “rapid” acetylators) and are a well-known risk factor for UBC. The A/A genotype tags the slow phenotype. Increased risks were observed in current smokers (OR=1.25). Rothman et al., 2010 NAT2 tagSNP rs1495741[A/A] showed an excellent specificity (0.94) regarding the phenotype but was outperformed by the common NAT2 genotype (1.00) and a 2-SNP genotype (1.00) based on the known NAT2 SNPs in Caucasians.  Selinski et al., 2011  EXCLI Journal 2012;11:743-747 – ISSN 1611-2156 Received: November 07, 2012, published: November 14, 2012  745 Table 1 (cont.): Currently confirmed genetic variants that are associated with bladder cancer risk.  Polymorphisms and related genes are printed bold, risk alleles are given in brackets. Key message Reference  Rs8102137[C] near CCNE1 (cyclin E1) involved in the cell cycle G1/S phase transition was associated with UBC in a GWAS (OR=1.13). CCNE1 over-expression seems to be associated with tu-morigenesis and UBC prognosis.  Rothman et al., 2010 Rs1014971[T] 25 kb from CBX6 (chromobox homolog 6) and 64 kb from APOBEC3A (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3A) was associated with UBC in a GWAS (OR=1.14). Rothman et al., 2010 The well-known increased UBC risk of GSTM1 null genotypes was confirmed in a GWAS (OR=1.47). Rothman et al., 2010 Rs1058396[G] in SLC14A1 (solute carrier family 14 (urea trans-porter), member 1 (Kidd blood group)) exon 8 leading to an amino acid exchange and rs17674580[T] in an intron of the same gene are associated with UBC in a GWAS (OR=1.14; OR=1.17). SLC14A1 is involved in maintenance of a constant urea concentration gradient in the kidney. Rs1058396 (D280N) determines two alleles of the Kidd blood system. Rs17674580 explained the effect of rs1058396. Rafnar et al., 2011   REFERENCES Arand M, Mühlbauer R, Hengstler J, Jäger E, Fuchs J, Winkler L et al. A multiplex polymerase chain reaction protocol for the simultaneous analysis of the glutathione S-transferase GSTM1 and GSTT1 polymor-phisms. Anal Biochem 1996;236:184-6.  Binder H, Müller T, Schwender H, Golka K, Steffens M, Hengstler JG et al. Cluster-localized sparse logistic regression for SNP data. Stat Appl Genet Mol Biol 2012 Aug 14;11(4). pii: /j/sagmb.2012.11.issue-4/1544-6115.1694/1544-6115.1694.xml. http://dx.doi.org/10.1515/1544-6115.1694  Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. GLOBOCAN 2008 v2.0, Cancer incidence and mortality worldwide: IARC CancerBase No. 10. Lyon: International Agency for Research on Cancer, 2010. Available from: http://globocan.iarc.fr, accessed on Nov 09, 2012.  Fu YP, Kohaar I, Rothman N, Earl J, Figue-roa JD, Ye Y et al. Common genetic vari-ants in the PSCA gene influence gene ex-pression and bladder cancer risk. Proc Natl Acad Sci U S A 2012;109:4974-9. Golka K, Prior V, Blaszkewicz M, Cascorbi I, Schöps W, Kierfeld G et al. 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Genetic variants confer susceptibility to urinary bladder cancer

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Genetic variants confer susceptibility to urinary bladder cancer

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