Characteristics of study participants are presented in . Call rates for each genotypic assay were ≥96.9%. Among non-Hispanic white and Chinese participants, BD11934905 was monomorphic (GG genotype). For the remaining 8 SNPs, genotype–bladder cancer associations are presented in as per allele RR estimates, calculated using a log-additive model of genetic risk.
Characteristics of non-Hispanic white participants in Los Angeles and Chinese participants in Shanghai
Associations between genotypes defined by cancer-related SNPs on 8q24 and bladder cancer risk
Genotypes defined by rs7000448, rs6983267, rs6983561, rs13254738, rs13281615, and rs10090154 did not seem to be related to bladder cancer risk among either non-Hispanic whites or Chinese. To our knowledge, other investigators have not previously reported on the null association between rs7000448 and bladder cancer risk, but consistent with these results, Kiemeney et al. and Wu et al. (14
) reported no association between bladder cancer risk and genotypes defined by rs6983267 or additional SNPs, each in perfect (r2
= 1.00) or extremely strong (r2
= 0.97) linkage disequilibrium with rs6983561, rs13281615, or rs10090154. Thus, these SNPs do not seem to influence bladder cancer risk, even though abundant data indicate that genotypes defined by each are associated with risk of 1 or more other cancers.
We found the rs7008482 G allele, previously shown to be associated with prostate cancer risk (12
), to be associated with a marginally significant (P
= 0.028) risk of bladder cancer among non-Hispanic whites [RR = 1.23 (95% CI, 1.02–1.48)], to our knowledge the first report of this association, which we did not observe among Chinese.
The T allele of rs9642880 already implicated in bladder cancer (14
) was associated with risk in both groups [RR = 1.43 (95% CI, 1.20–1.70) among non-Hispanic whites; RR = 1.20 (95% CI, 1.00–1.45) among Chinese]. This association was highly significant in overall data (P
= 0.000024). In further analyses we estimated the RR associated with GT to be 1.72 (95% CI, 1.28–2.32) and that with TT to be 2.05 (95% CI, 1.45–2.92), compared with the GG genotype. These results confirm the association of rs9642880 T with bladder cancer risk, among both high-risk non-Hispanic whites and low-risk Chinese.
To explore possible heterogeneity of the rs9642880–bladder cancer association, we conducted stratified analyses, results of which appear in . The effect of rs9642880 T seemed greater at older ages and among females, but differences were not statistically significant. Among non-Hispanic whites, however, effect of this allele was greater among nonsmokers [RR = 1.74 (95% CI, 1.21–2.50)] and former smokers [RR = 1.57 (95% CI, 1.18–2.09], and nearly absent among current smokers [RR = 0.98 (95% CI, 0.70–1.39)]. Among Chinese, although we did not observe this monotonic pattern, the effect of rs9642880 was also greater in nonsmokers and former smokers. Tobacco smoking, the primary established risk factor for bladder cancer, is responsible for approximately half of all bladder cancer among non-Hispanic whites. However, little is known about etiology of bladder cancer among nonsmokers. The possibility suggested by these results that rs9642880 T may predispose to bladder cancer among nonsmokers therefore deserves further investigation.
Associations between rs9642880 T allele and bladder cancer risk by strata of selected risk factors
Regular use of NSAIDs is rare among Chinese in Shanghai and was not determined for Chinese participants. Among non-Hispanic whites, the rs9642880–bladder cancer association seemed to be somewhat stronger among users [RR = 1.58 (95% CI, 1.16–2.14)] than among nonusers [RR = 1.27 (95% CI, 1.01–1.62)] of NSAIDs, although the corresponding interaction term was not statistically significant (P = 0.17). Based on our earlier finding that a history of regularly using NSAIDs is associated with lesser risk of bladder cancer, we have postulated that inflammation may influence bladder carcinogenesis. Under this scenario, a stronger effect of rs9642880 among users of NSAIDs would motivate us to consider a role for rs9642880 in inflammatory processes.
Using tumor stage and grade as indicators of prognosis, Kiemeney et al. (14
) reported notably higher frequency rs9642880 T among patients with “low-risk” (Ta/G1 or Ta/G2) papillary tumors confined to the bladder mucosa and not poorly differentiated, compared with those with “high-risk” (other stage/grade) tumors poorly differentiated or with lamina propria invasion. Using identical definitions, we observed per allele RRs of 1.64 (95% CI, 1.32–2.03) for “low risk” and 1.19 (95% CI, 0.95–1.50) for “high-risk” tumors; history of smoking seemed to be neither a modifier nor a confounder of these associations. Because stage and grade data were not available for Chinese cases at the time of this analysis, inferences relying on these variables—both from data presented here and earlier reports—are at present limited to individuals of European ancestry. The estimated ratio of RRs (based on case–case analysis) was 1.37 (95% CI, 1.05–1.79). Combining this result with the like RR reported by Kiemeney et al., we estimated the summary RR to be 1.20 (95% CI, 1.04–1.40), suggesting particular importance of rs9642880 T in noninvasive papillary bladder tumors. Wolff et al. (19
) noted that most molecular alterations identified in tumors of this type can activate the ras mitogen-activated protein kinase (MAPK) pathway. Intriguingly, a key effect of activating this pathway is induction of the proto-oncogene MYC
, located 30-kb downstream from rs9642880.
is the annotated gene most closely located to each cancer-associated 8q24 SNP identified to date, all of which are non–protein-coding variants. The possibility that these variants influence cancer risk by regulating MYC
or another cancer-related gene is now a topic of intense investigation. Molecular studies have focused on 8q24 variants associated with other cancers but reported here and by others (14
) to be unassociated with bladder cancer risk. These efforts provide compelling evidence of transcriptional enhancer function (20
) and long-range physical interaction between a more distant colorectal cancer risk region containing rs6983267 and MYC
The specific and consistent association of bladder cancer with rs9642880 in multiple racial-ethnic groups, together with its location between likely enhancer sequence (20
) and MYC
, make functional analysis of the region containing rs9642880 a new priority in bladder cancer research.