Abstract 3436: Circadian rhythm dysregulation with risk of gastrointestinal cancers: A large-scale prospective analysis

Abstract Introduction: The incidence of multiple gastrointestinal (GI) cancers has been rising among younger adults with unknown etiology. Circadian rhythm dysregulation due to increasing exposures to artificial lighting, irregular work hours, and frequent travel, has been recently linked with multiple diseases. Disruption of the circadian clock drives Apc LOH to hyperactivate Wnt signaling and enhances MYC-dependent glycolytic metabolism to accelerate colorectal cancer progression. However, the association between circadian rhythm dysregulation, quantified by relative amplitude (RA) –a parameter derived from rest-activity patterns, and risk of colorectal and other GI cancers has not been evaluated in epidemiologic studies. Methods: We prospectively examined the associations between RA and risk of incident GI cancers among 87, 653 UK Biobank participants who wore an Axivity AX3 triaxial accelerometer over 7 days (2013-15) with follow-up to 2021. RA was derived and averaged across all valid days, using the difference between the mean activity levels during the most active 10-hour period and the least active 5-hour period. Cox models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs). Results: During 512, 074 person-years, 1, 079 incident GI cancer cases occurred. After multivariable adjustment, lower RA was associated with an increased risk of overall GI cancer (RR per SD standard deviation = 1. 12, 95% CI 1. 04-1. 21, P for trend = 0. 01). Compared to individuals in the highest tertile (T1), those with RA in the lowest tertile (T3) had a 25% increased risk of overall GI cancer (RR = 1. 25, 95% CI 1. 05-1. 50). The positive associations with GI cancers were mainly driven by gastric cancer (RR per SD = 1. 33, 95% CI 1. 02-1. 74, P for trend= 0. 04) and colon cancer (RR per SD = 1. 13, 95% CI 1. 00-1. 28, P for trend = 0. 03). Conclusion: In this large-scale, prospective analysis of accelerometer data, circadian rhythm dysregulation was associated with subsequent risk of GI cancers, primarily gastric and colon cancer. To our knowledge, this is among the first population-based studies reporting the positive link between circadian rhythm dysregulation with cancer risk. Citation Format: Yi Kang, Shinghei Mok, Xiaoyu Zong, Yin Cao. Circadian rhythm dysregulation with risk of gastrointestinal cancers: A large-scale prospective analysis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 3436.