Role of Circadian Factors in Inflammation and Colorectal Adenoma Risk

Colorectal cancer (CRC) is among the most common and deadly forms of cancer. In South Carolina, our group
has documented racial CRC disparities that exceed national rates. Most colon tumors arise from adenomas
(adenomatous polyps) that are detected via a screening colonoscopy. Gastrointestinal (GI) inflammation and
aberrant DNA methylation are key processes driving adenoma formation and CRC risk. Sleep loss and
circadian rhythm disruption can induce inflammation, alter DNA methylation, and increase CRC risk. African-
Americans (AAs) differ from European-Americans (EAs) in their endogenous circadian timing, and they are
more likely than EAs to have poor sleep and excessive stress (allostatic overload or ‘weathering’). This case-
control study will test the hypothesis that disruption of circadian processes and sleep is associated with
inflammation and adenoma risk among AA and EA patients receiving a screening colonoscopy. Molecular
timekeeping is controlled by ‘clock genes’ that regulate circadian gene expression via epigenetic mechanisms.
Clock genes can modulate inflammation (e.g., TNFα, IL-6 expression), and they act as tumor suppressors
(e.g., the ‘Period’ or PER genes). Our research suggests that genetic variation or aberrant methylation in PER
genes is associated with increased adenoma risk, and that sleep disorders can increase CRC risk. Melatonin is
a clock-regulated hormone that suppresses GI inflammation and inhibits colon tumor growth by binding to its
cellular receptors (MT-1, RORα). This study will characterize biobehavioral circadian disruption indicators
(sleep disturbances, social jet lag, fatigue, stress), along with key molecular correlates (PER3 genotype and
methylation of: clock genes [PER1, PER2, PER3]; clock-controlled genes [MT-1, RORα, TNFα, IL-6]; and
global DNA methylation [LINE-1]) to determine their role in inflammation and adenoma risk. A biobehavioral
framework will address the following Specific Aims: 1) Conduct a case-control study among patients
undergoing a screening colonoscopy to determine whether circadian disruption indicators (DNA methylation,
biobehavioral, genetic) are associated with adenoma case status relative to controls, and if the relationship is
modified by race (N=1,000; 400 cases, 600 controls); 2) Determine if circadian disruption indicators are
associated with inflammation in normal GI tissue (TNFα, IL-6 mRNA expression); 3) Determine whether
behavioral and molecular circadian disruption indicators are related; 4) Among adenoma cases, determine if
methylation of candidate circadian genes in adenomas differs from normal GI tissue. Our team has a strong
track record of providing high quality colonoscopy services and in engaging AA and EA communities in
research. Prospective data collection (relative to colonoscopy) and the use of valid, quantitative biobehavioral
and molecular measures will limit the potential introduction of bias. This study will rigorously examine
circadian-based behavioral and molecular risk factors as they relate to GI inflammation and colorectal
adenoma risk. Circadian-based risk factors may serve as novel, modifiable targets for CRC prevention.

Grant Number: 5R01CA231321-06
NIH Institute/Center: NIH
Principal Investigator: James Burch