Urinary bladder cancer risk variants: recent findings and new challenges of GWAS and confirmatory studies

Abstract

polymorphisms (SNPs) associated with a moderate UBC risk at sixteen chromosomal locations, besides GSTM1 (Table 1; reviews, see Golka et al. 2011; Dudek et al. 2013). While most of them could be confirmed in independent follow-up case–control series, novel UBC risk SNPs are still requiring validation. It can be assumed that the most relevant loci are discovered now as the size of the GWAS is considerable large with more than 6,900 cases and 45,000 controls (Kiemeney et al. 2010; rothman et al. 2010; rafnar et al. 2011; Figueroa et al. 2014a, b), and the density of the SNP chips combined with highly accurate imputation algorithms results in a sufficient representation of the genetic variation. Subsequent fine-mapping studies aim to identify the functional relevant genetic variants that are in linkage disequilibrium with the initial findings that are often located in non-coding regions more than 20 kb and several haploblocks apart of the next genes (review: Dudek et al. 2013; see also Selinski 2013). Tang et al. (2012), and Fu et al. (2012) used this approach to localize the genetic variants explaining the bladder cancer risk associated with SNPs in the UGTA1 and PSCA gene, respectively (Wu et al. 2009; rothman et al. 2010). however, further finemapping and functional studies are required to elucidate the functional relationship between polymorphism and disease for most of the SNPs. Currently, subgroup analyses, e.g., restricted to smokers or high-grade tumors, are becoming more and more relevant. First results of a GWAS on SNPs that interact with smoking habits suggest at least two novel loci that modify UBC risk in non-smokers or in smokers (Figueroa et al. 2014a). Besides, discovery of novel loci in subgroups stratification and interaction analyses of known risk factors indicate how and to which extend genetic risk factors modify bladder cancer risk in presence or absence of exogenous risk factors, e.g., smoking (Garcia-Closas et al. 2013) and Urinary bladder cancer (UBC) is the fourth most common cancer in men and the fourteenth most common cancer in women in western europe (Ferlay et al. 2013). Approximately 50 % of the UBC cases are caused by cigarette smoking (Schwender et al. 2012; Burger et al. 2013). Further, 7.1–20 % of the bladder cancer cases can be attributed to occupational exposure to aromatic amines and polycyclic aromatic hydrocarbons (Golka et al. 2004, 2009, 2012; Delclos and Lerner 2008; rushton et al. 2012; Burger et al. 2013; Carreon et al. 2014). Genetic risk factors explain about 31 % of the bladder cancer cases (Lichtenstein et al. 2000). As segregation analysis in 1,193 families failed to identify a major gene (Aben et al. 2006), a polygenetic basis of bladder cancer can be assumed. This is consistent with recent findings of a number of polymorphisms each conferring a small to moderate UBC risk (Golka et al. 2011; Selinski 2012). Polymorphisms of phase II metabolizing enzymes are well known to increase bladder cancer risk and to modulate the effect of bladder carcinogen exposure via smoking and occupation (Garcia-Closas et al. 2005; Golka et al. 2009; Moore et al. 2011). Most relevant is the deletion variant of glutathione S-transferase M1 (GSTM1) (Arand et al. 1996; Golka et al. 1997, 2009; Garcia-Closas et al. 2005; Ovsiannikov et al. 2012) and polymorphisms in the N-acetyltransferase 2 (NAT2) gene resulting in a reduced acetylation capacity (Golka et al. 1996, 2002; Moore et al. 2011; Selinski et al. 2011, 2013). Meanwhile, genome-wide association studies (GWAS) have identified a number of novel single nucleotide