The post GWAS era: strategies to identify gene-gene and gene-environment interactions in urinary bladder cancer

摘要

Bladder cancer is a smoking- and occupational exposure-related disease with a substantial genetic component (Boffetta, 2008; Golka et al., 2012; Roth et al., 2012; Rushton et al., 2012; Schwender et al., 2012; Burger et al., 2013). Approximately 30 % of all urinary bladder cancer cases can be attributed to genetic risk factors (Lichtenstein et al., 2000; Selinski, 2012; Hammad, 2013). Both family studies and large genome-wide association analyses support a polygenetic basis for urinary bladder carcinomas, mainly because there is no evidence for a major gene (Aben et al., 2006; Kiemeney, 2008; Kiemeney et al., 2010; Rafnar et al., 2011; Stewart and Marchan, 2012; Bolt, 2013a, b), and all known susceptibility variants show moderate risks (Grotenhuis et al., 2010; Lehmann et al., 2010; Golka et al., 2011; Selinski et al., 2012a, b; Dudek et al., 2013; Selinski, 2014). Several of these moderate-risk variants, especially those categorized as phase II metabolism genes, have been shown to modulate bladder cancer risk depending on exposure to bladder carcinogens, in particular, aromatic amines and polycyclic aromatic hydrocarbons (Garcia-Closas et al., 2005, 2013; Golka et al., 2009; Rothman et al., 2010; Moore et al., 2011; Selinski et al., 2011, 2012b). These gene-environment interactions are well-investigated for several phase II genes, including the deletion variant of glutathione- S-transferase M1 (GSTM1) and the Nacetyltransferase 2 (NAT2) polymorphisms, both of which are particularly relevant in the presence of their carcinogenic substrates due to occupational or tobacco smoke exposure (Engel et al., 2002; Golka et al., 2002, 2008, 2009; Garcia-Closas et al., 2005; Kopps et al., 2008; Hengstler, 2010; Moore et al., 2011; Ovsiannikov et al., 2012; Selinski, 2013, 2014; Selinski et al., 2013a, b, 2014). Current studies focus on a broader range of polymorphisms identified by genome-wide association studies (GWAS) and the interaction of these polymorphisms with tobacco smoke exposure. Garcia-Closas et al. (2013) investigated the interaction between smoking habits and the well-known panel of eleven single nucleotide polymorphisms (SNPs) from GWAS, in addition to GSTM1, in studies, which were all part of the NCI bladder cancer GWAS. The NCI bladder cancer GWAS led to the discovery of several of these bladder cancer susceptibility SNPs. The authors found additive interactions between exposure and six of the variants, in particular, rs1495741 (NAT2), rs17863783 (UDP glucuronosyltransferase 1 family, polypeptide A6 UGT1A6), GSTM1, rs2294008 (prostate stem cell antigen PSCA), rs9642880 (v-myc avian myelocytomatosis viral oncogene homolog MYC) and rs1014971 (chromobox homolog 6 CBX6, apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3A APOBEC3A) (Garcia-Closas et al., 2013). Figueroa et al. (2014) searched genome-wide for SNP × smoking interactions in the same multicentric case-control series.