0031 INHERITED VARIATION IN CIRCADIAN RHYTHM GENES AND RISKS OF PROSTATE CANCER AND THREE OTHER CANCER SITES IN COMBINED CANCER CONSORTIA

Abstract

Introduction: Circadian disruption has been linked to carcinogenesis in animal models and to breast cancer in humans. However, the evidence for other types of cancer is inconclusive. Variations in genes involved in circadian rhythm provide a tool to investigate such associations. Methods: We examined associations of genetic variation in nine core circadian rhythm genes and six melatonin pathway genes with risk of colorectal, lung, ovarian and prostate cancers using genome-wide association studies (GWAS) from GAME-ON. The major results for prostate cancer were replicated in PLCO, and for colorectal cancer in GECCO. The total number of cancer cases and controls was 15,838/18,159 for colorectal, 14,818/14,227 for prostate, 12,537/17,285 for lung and 4,369/9,123 for ovary. For each cancer site, we used the SNP summary statistics for the candidate gene regions imputed to 1000 Genomes. Gene-level and pathway-level analyses were conducted using the summary-based Adaptive Rank Truncated Product method (sARTP). Results: Aggregate genetic variation in circadian rhythm and melatonin pathways were significantly associated with the risk of prostate cancer in data combining GAME-ON and PLCO, after Bonferroni correction (Ppathway<0.00625). The two most significant genes were NPAS2 (Pgene=0.0062) and AANAT (Pgene=0.00078); the latter being significant after Bonferroni correction. For colorectal cancer, we observed a suggestive association with the circadian rhythm pathway in GAME-ON (Ppathway=0.021), that was not confirmed in GECCO (Ppathway=0.76) or the combined data (Ppathway=0.17). No other association was observed for the other cancer sites. Conclusion: These findings support a potential role for circadian rhythm and melatonin pathways in prostate carcinogenesis. Further functional studies are needed to better understand the underlying biologic mechanisms.