The ADH3(1-1) genotype appears to substantially increase the risk of ethanol-related oral cancer, thus providing further evidence for the carcinogenicity of acetaldehyde.

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Novelty & Impact:We found a significant association of circadian rhythm and melatonin 2 pathway genes with prostate cancer risk, at the gene and pathway level, after taking multiple 3 comparisons into account. The sample size is the largest to our knowledge, with a further 4 replication in an independent data. This study provides evidence in support of a role for circadian 5 rhythm and melatonin pathways in prostate carcinogenesis. 6Word count: 267 in abstract; 2701 in text. Circadian disruption has been linked to carcinogenesis in animal models, but the evidence in 3 humans is inconclusive. Genetic variation in circadian rhythm genes provides a tool to 4 investigate such associations. We examined associations of genetic variation in nine core 5 circadian rhythm genes and six melatonin pathway genes with risk of colorectal, lung, ovarian 6 and prostate cancers using data from the Genetic Associations and Mechanisms in Oncology 7 (GAME-ON) network. The major results for prostate cancer were replicated in the Prostate, were significantly associated with the risk of prostate cancer in data combining GAME-ON and 16 PLCO, after Bonferroni correction (P pathway <0.00625). The two most significant genes were 17 NPAS2 (P gene =0.0062) and AANAT (P gene =0.00078); the latter being significant after Bonferroni 18 correction. For colorectal cancer, we observed a suggestive association with the circadian rhythm 19 pathway in GAME-ON (P pathway =0.021); this association was not confirmed in GECCO 20(P pathway =0.76) or the combined data (P pathway =0.17). No association was observed for ovarian and 21 lung cancer. These findings support a potential role for circadian rhythm and melatonin pathways