Despite many years of candidate gene studies testing for GxE in cancer, there are only a few notable replicated and widely-agreed-upon examples of successes (e.g. NAT2, smoking and bladder cancer; ALDH2, alcohol and esophageal cancer) [Brooks, et al. 2009; Garcia-Closas, et al. 2013; Wu, et al. 2012]. Hundreds of studies reporting analyses of GxE interaction in cancer were published before the advent of GWAS, but most suffered from problems that plagued candidate gene studies of marginal association, including small sample sizes, insufficiently stringent thresholds for statistical significance (needed to account for multiple testing and low priors), incomplete genetic coverage, and publication bias [Hirschhorn and Altshuler 2002; Ioannidis 2005; Wacholder, et al. 2004]. For example, of 407 studies examining GxE interactions in breast cancer published before May 2011, 307 (75%) reported a statistically significant GxE interaction—a strikingly high proportion, suggesting most are false positives.
