Genetic variants confer susceptibility to urinary bladder cancer: an updated list of confirmed polymorphisms



Urinary bladder cancer is the 7^th most common cancer in Western Europe (Ferlay et al., 2012[3]). The most relevant risk factors are occupational exposure to aromatic amines and polycyclic aromatic hydrocarbons as well as cigarette smoking (Golka et al., 2012[6], 2009[5], 2004[11]; Schwender et al., 2012[23]). 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[18]; Golka et al., 2009[5], 1997[9]; Arand et al., 1996[1]) and polymorphisms in the N-acetyltranferase 2 (NAT2) gene leading to a reduced acetylation capacity (Selinski et al., 2011[24]; Moore et al., 2011[16]; Golka et al., 2002[7], 1996[8]), and currently their influence on prognosis is investigated (Roth et al., 2012[21]; Nørskov et al., 2011[17]). Recently, genome-wide association studies (GWAS) have identified several novel nucleotide polymorphisms (SNPs) as associated with urinary bladder cancer (UBC) risk and most of them could be confirmed in independent follow-up case-control series (review: Golka et al., 2011[10]; Table 1(Tab. 1) [References in Table 1: Kiemeney et al., 2008[13]; Golka et al., 2009[5]; Kiemeney et al., 2008[13]; Lehmann et al., 2010[14]; Rafnar et al., 2009[19]; Wu et al., 2009[27]; Fu et al., 2012[4]; Kiemeney et al., 2010[12]; Rothman et al., 2010[22]; Selinski et al., 2012[25]; Tang et al., 2012[26]; Rothman et al., 2010[22]; Selinski et al., 2011[24]; Rothman et al., 2010[22]; Rothman et al., 2010[22]; Rothman et al., 2010[22]; Rafnar et al., 2011[20]). 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[20]; Kiemeney et al., 2010[12]; Rothman et al., 2010[22]), 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 additive risks? How high is the population attributable risk of the combined influence of all polymorphisms? And how important is the combined genetic risk compared to the risk attributable to cigarette smoking and occupational exposure to bladder carcinogens? Considering the recent progress in genome-wide association studies it can be expected that answers to these questions will soon be available.

Table 1. Currently confirmed genetic variants that are associated with bladder cancer risk. Polymorphisms and related genes are printed bold, risk alleles are given in brackets.

First analyses beyond the standard single SNP analyses in case-control designs yield promising results (Binder et al., 2012[2]; Menashe et al., 2012[15]; Schwender et al., 2012[23]).