Guest editorial
Discovering urinary bladder cancer risk variants: Status quo after almost ten years of genome-wide association studies
Silvia Selinski1
1Leibniz Research Centre for Working Environment and Human Factors (IfADo)
EXCLI J 2017;16:Doc1288
About ten years ago Kiemeney and colleagues (2008[24]) published the first genome-wide association study (GWAS) discovering two novel single nucleotide polymorphisms (SNPs) near MYC (rs9642880) and TP63 (rs710521) associated with urinary bladder cancer (UBC) risk. Meanwhile, further GWAS and candidate gene studies identified and confirmed a number of susceptibility variants for UBC (Selinski, 2012[37], 2013[38], 2014[39]; Dudek et al., 2013[4]; Selinski et al., 2013[41]; Golka et al., 2011[18]). Currently, fifteen genomic regions seem to play a major role in development of this disease (Table 1(Tab. 1); References in Table 1: Figueroa et al., 2014[8]; Fu et al., 2012[9]; Garcia-Closas et al., 2013[11]; Golka et al., 2009[13]; Grotenhuis et al., 2014[20]; Kiemeney et al., 2010[23]; Lehmann et al., 2010[26]; Nørskov et al., 2011[29]; Rafnar et al., 2014[32]; Rothman et al., 2010[34]; Selinski et al., 2012[44]; Tang et al., 2012[45]; Wang et al., 2014[46]; Wu et al., 2009[47]). It can be assumed that almost all relevant polymorphisms have been discovered now. The most recent UBC GWAS of Figueroa et al. (2016[7]) required 15,058 cases and 286,270 controls to discover a further susceptibility region at 13q34 (MCF2L gene), including the Icelandic and the Dutch GWAS (Gudbjartsson et al., 2015[21]; Kiemeney et al., 2008[24]). The odds ratios of the most recent UBC risk SNPs are rather small, e.g. the MCF2L intron variant rs4907479, with the strongest signal in the 2016 fine-mapping study of Figueroa et al. (2016[7]) resulted in an odds ratio (OR) of 1.13.
Several UBC risk variants are particularly relevant in persons exposed to bladder carcinogens - mainly by tobacco smoke (Burger et al., 2013[1]; Garcia-Closas et al., 2005[10], 2011[12], 2013[11]; Selinski et al., 2013[41]; Moore et al., 2011[28]) but also by occupation and environment (Ebbinghaus et al., 2017[5]; Höhne et al., 2017[22]; Krech et al., 2017[25]; Lukas et al., 2017[27]; Carreón et al., 2014[2]; Golka et al., 2012[14], 2009[13], 2004[19], 2002[15], 1997[17], 1996[16]; Delclos and Lerner, 2008[3]; Ovsiannikov et al., 2012[30]; Rushton et al., 2012[35]). However, currently no particular variant that is only relevant in exposed persons could be identified and replicated in GWAS. In 2014, Figueroa et al. (2014[6]) identified two variants in a genome-wide smoking ⨯ SNP interaction study -rs1711973 (FOXF2) relevant for never smokers and rs12216499 (RSPH2-TAGAP-EZR) in ever smokers, but both could not be confirmed using a large replication series (Figueroa et al., 2016[7]). Nevertheless, interaction analyses and stratification regarding smoking habits and cancer invasiveness are promising future approaches to uncover further susceptibility variants that are relevant for particular subgroups of the UBC patients.
A further challenge is a genome-wide search for variants associated with bladder cancer recurrence and progression. This requires a large number of UBC patients with follow-up of several years after first diagnosis. However, it can be assumed that variants relevant for UBC development are also associated with UBC recurrence. Recurrence of this tumor occurs in approximately half of the patients with a median recurrence-free time of almost one year. Selinski et al. (2017[43]) showed that the ultra-slow N-acetyltransferase 2 (NAT2) genotype was associated with a significant reduction of recurrence-free time (8.4 months) compared to rapid acetylators (11 months) and an increased recurrence risk (66 % vs. 50 %, OR=1.89, 95 % CI = 1.06-3.38). Effects were more pronounced in ultra-slow smokers (7.9 months, 73 %) indicating the relevance of gene-environment interaction also for prognosis. Correspondingly, Lukas et al. (2017[27]) showed in a series of 143 UBC cases with suspected occupational bladder cancer the importance of co-occurring susceptibility variants, particularly co-occurring GSTM1 negative and rs11892031[A/A] for UBC recurrence. They discovered that UBC cases with an elevated number of risk alleles had a significantly shorter median relapse-free time of 8 months compared to cases with few risk alleles.
According to the different importance of several genetic variants depending on exposure to bladder carcinogens, e.g. GSTM1 and NAT2, different variant combinations seem to play a major role in smokers and never smokers (Selinski et al., 2017[40]; Schwender et al., 2012[36]. Recently, Selinski et al. (2017[40]) identified and replicated in a large multi-centric case-controls series (discovery series: 2969 cases / 3285 controls, replication series: 2080 cases / 2167 controls) four-variant combinations out of twelve well-known UBC risk variants. The highest odds ratios were found in never smokers with the best combination (rs1014971[AA] ⨯ rs1058396[AG,GG] ⨯ rs11892031[AA] ⨯ rs8102137[CC,CT]) resulting in an OR of 2.59 (95 % CI = 1.93-3.47; P = 1.87 ⨯ 10-10, frequency in never smoking cases: 25 %). Odds ratios of the best combinations found in smokers were clearly lower (current smokers: 1.56, former: 2.13, ever: 1.55) and different variant combinations were relevant, especially GSTM1, rs1058396 (SLC14A1) and rs11892031 (UGT1A) combinations in current and rs9642880 (MYC), rs1495741 (NAT2) and rs8102137 (CCNE1) combinations in former smokers (Selinski et al., 2017[40]).
References
1.
Burger M, Catto JWF, Dalbagni G, Grossman HB, Herr H, Karakiewicz P, et al. Epidemiology and risk factors of urothelial bladder cancer. Eur Urol. 2013;63:234-41.2.
Carreón T, Hein MJ, Hanley KW, Viet SM, Ruder AM. Bladder cancer incidence among workers exposed to o-toluidine, aniline and nitrobenzene at a rubber chemical manufacturing plant. Occup Environ Med. 2014;71:175-82. 3.
Delclos GL, Lerner SP. Occupational risk factors. Scand J Urol Nephrol. 2008;42:58-63.4.
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.
Ebbinghaus D, Bánfi G, Selinski S, Blaszkewicz M, Bürger H, Hengstler JG, et al. Polymorphisms of xenobiotic metabolizing enzymes in bladder cancer patients of the Semmelweis University Budapest, Hungary. J Toxicol Environ Health A. 2017;80:423-9. 6.
Figueroa JD, Han SS, Garcia-Closas M, Baris D, Jacobs EJ, Kogevinas M, et al. Genome-wide interaction study of smoking and bladder cancer risk. Carcinogenesis. 2014;35:1737-44.7.
Figueroa JD, Middlebrooks CD, Banday AR, Ye Y, Garcia-Closas M, Chatterjee N, et al. Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry. Hum Mol Genet. 2016;25:1203-14.8.
Figueroa JD, Ye Y, Siddiq A, Garcia-Closas M, Chatterjee N, Prokunina-Olsson L, et al. Genome-wide association study identifies multiple loci associated with bladder cancer risk. Hum Mol Genet. 2014;23:1387-98.9.
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;109:4974-9.10.
Garcia-Closas M, Malats N, Silverman D, Dosemeci M, Kogevinas M, Hein DW, et al. NAT2 slow acetylation, GSTM1 null genotype, and risk of bladder cancer: results from the Spanish Bladder Cancer Study and meta-analyses. Lancet. 2005;366:649-59. 11.
Garcia-Closas M, Rothman N, Figueroa JD, Prokunina-Olsson L, Han SS, Baris D, et al. Common genetic polymorphisms modify the effect of smoking on absolute risk of bladder cancer. Cancer Res. 2013;73:2211-20.12.
Garcia-Closas M, Ye Y, Rothman N, Figueroa JD, Malats N, Dinney CP, et al. A genome-wide association study of bladder cancer identifies a new susceptibility locus within SLC14A1, a urea transporter gene on chromosome 18q12.3. Hum Mol Genet. 2011;20:4282-9.13.
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 Genom. 2009;19:903-6.14.
Golka K, Kopps S, Prager HM, Mende S v, Thiel R, Jungmann O, et al. Bladder cancer in crack testers applying azo dye-based sprays to metal bodies. J Toxicol Environ Health A. 2012;75:566-71.15.
Golka K, Prior V, Blaszkewicz M, Bolt HM. The enhanced bladder cancer susceptibility of NAT2 slow acetylators towards aromatic amines: a review considering ethnic differences. Toxicol Lett. 2002;128:229-41. 16.
Golka K, Prior V, Blaszkewicz M, Cascorbi I, Schöps W, Kierfeld G, et al. Occupational history and genetic N-acetyltransferase polymorphism in urothelial cancer patients of Leverkusen, Germany. Scand J Work Environ Health. 1996;22:332-8.17.
Golka K, Reckwitz T, Kempkes M, Cascorbi I, Blaskewicz M, Reich SE, et al. N-Acetyltransferase 2 (NAT2) and glutathione S-transferase µ (GSTM1) in bladder-cancer patients in a highly industrialized area. Int J Occup Environ Health. 1997;3:105-10.18.
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. 19.
Golka K, Wiese A, Assennato G, Bolt HM. Occupational exposure and urological cancer. World J Urol. 2004;21:382-91. 20.
Grotenhuis AJ, Dudek AM, Verhaegh GW, Witjes JA, Aben KK, van der Marel SL, et al. Prognostic relevance of urinary bladder cancer susceptibility Loci. PLoS ONE. 2014;9:e89164.21.
Gudbjartsson DF, Helgason H, Gudjonsson SA, Zink F, Oddson A, Gylfason A, et al. Large-scale whole-genome sequencing of the Icelandic population. Nat Genet. 2015;47:435-44.22.
Höhne S, Gerullis H, Blaszkewicz M, Selinski S, Hengstler JG, Otto T, et al. N-acetyltransferase 1*10 genotype in bladder cancer patients. J Toxicol Environ Health A. 2017;80:417-22. 23.
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. 24.
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;40:1307-12.25.
Krech E, Selinski S, Blaszkewicz M, Bürger H, Kadhum T, Hengstler JG, et al. Urinary bladder cancer risk factors in an area of former coal, iron, and steel industries in Germany. J Toxicol Environ Health A. 2017;80:430-8. 26.
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;84:967-78.27.
Lukas C, Selinski S, Prager HM, Blaszkewicz M, Hengstler JG, Golka K. Occupational bladder cancer: Polymorphisms of xenobiotic metabolizing enzymes, exposures, and prognosis. J Toxicol Environ Health A. 2017;80:439-52. 28.
Moore LE, Baris DR, Figueroa JD, Garcia-Closas M, Karagas MR, Schwenn MR, et al. GSTM1 null and NAT2 slow acetylation genotypes, smoking intensity and bladder cancer risk: results from the New England bladder cancer study and NAT2 meta-analysis. Carcinogenesis. 2011;32:182-9.29.
Nørskov MS, Frikke-Schmidt R, Bojesen SE, Nordestgaard BG, Loft S, Tybjærg-Hansen A. Copy number variation in glutathione-S-transferase T1 and M1 predicts incidence and 5-year survival from prostate and bladder cancer, and incidence of corpus uteri cancer in the general population. Pharmacogenomics J. 2011;11:292-9.30.
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;75:557-65.31.
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;41:221-7.32.
Rafnar T, Sulem P, Thorleifsson G, Vermeulen SH, Helgason H, Saemundsdottir J, et al. Genome-wide association study yields variants at 20p12.2 that associate with urinary bladder cancer. Hum Mol Genet. 2014;23:5545-57.33.
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;20:4268-81.34.
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;42:978-84.35.
Rushton L, Hutchings SJ, Fortunato L, Young C, Evans GS, Brown T, et al. Occupational cancer burden in Great Britain. Br J Cancer. 2012;107:S3-7.36.
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. Erratum in PLoS ONE. 2015;10:e0137937.37.
Selinski S. Genetic variants confer susceptibility to urinary bladder cancer: an updated list of confirmed polymorphisms. EXCLI J. 2012;11:743-7.38.
Selinski S. Highlight report: functional consequences of urinary bladder cancer risk variants. EXCLI J. 2013;12:1017-9.39.
Selinski S. Urinary bladder cancer risk variants: recent findings and new challenges of GWAS and confirmatory studies. Arch Toxicol. 2014;88:1469-75.40.
Selinski S, Blaszkewicz M, Ickstadt K, Gerullis H, Otto T, Roth E, et al. Identification and replication of the interplay of four genetic high risk variants for urinary bladder cancer. Carcinogenesis. 2017 (epub ahead of print). doi:10.1093/carcin/bgx102.41.
Selinski S, Blaszkewicz M, Ickstadt K, Hengstler JG, Golka K. Refinement of the prediction of N-acetyltransferase 2 (NAT2) phenotypes with respect to enzyme activity and urinary bladder cancer risk. Arch Toxicol. 2013;87:2129-39.42.
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;21:673-8.43.
Selinski S, Gerullis H, Otto T, Roth E, Volkert F, Ovsiannikov D, et al. Ultra-slow N-acetyltransferase 2 is associated with recurrence-free time in bladder cancer patients. Eur Urol. 2017;71:994-5.44.
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;86:1369-78.45.
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;21:1918-30.46.
Wang M, Chu H, Lv Q, Wang L, Yuan L, Fu G, et al. Cumulative effect of genome-wide association study-identified genetic variants for bladder cancer. Int J Cancer. 2014;135:2653-60.47.
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. Erratum in Nat Genet. 2009;41:1156.
Table 1: Currently confirmed polymorphisms that are associated with UBC risk, their association with bladder carcinogen exposure and prognosis (update of Selinski, 2014) according to Selinski (2014). Polymorphisms, associated genes and locations are printed in bold, risk alleles or genotypes are given in brackets.