Oxysterols are metabolites of cholesterol and intermediates in pathways for primary bile acid synthesis that regulate homeostasis of cholesterol, fatty acids, and glucose by interacting with widely expressed nuclear receptors. These metabolites are generated throughout the body, either enzymatically or from oxidative stress, and are detectable in peripheral circulation at concentrations much lower than total cholesterol. We previously reported that circulating 27-hydroxycholesterol (27-OHC), the most abundant oxysterol in circulation and an endogenous selective estrogen receptor modulator, may be a risk factor for colorectal adenomas. Here, we report on four other circulating oxysterols: 25-hydroxycholesterol (25-OHC), 24(S)-hydroxycholesterol (24(S)-OHC), 7ɑ-hydroxycholesterol (7ɑ-OHC), and 4β-hydroxycholesterol (4β-OHC). We used high-sensitivity liquid chromatography-mass spectrometry to measure oxysterol concentrations in fasting plasma collected at baseline from 1,440 participants of the Vitamin D/Calcium Polyp Prevention Study, a completed randomized clinical trial that enrolled men and women recently diagnosed with colorectal adenomas with follow-up timed to colonoscopic surveillance intervals. Advanced adenomas were defined as tubulovillous or villous lesions, ≥1 cm in diameter, with high-grade dysplasia, or invasive adenocarcinoma. Risk ratios (RR) with 95% confidence intervals (CI) of new colorectal adenomas occurring during follow-up were estimated using repeated-measures log-linear regression for log-transformed circulating oxysterols. Primary analyses adjusted for multiple potential confounding factors and the five circulating oxysterols simultaneously, including 27-OHC. One geometric standard deviation (SD) higher circulating 7ɑ-OHC at the time of initial adenoma diagnosis was associated with 9% and 20% higher subsequent risk of any adenomas and advanced adenomas, respectively (RR of any adenomas per SD circulating 7ɑ-OHC, 1.09; 95% CI, 1.03-1.15 and RR of advanced adenomas, 1.20; 95% CI, 1.04-1.39). The positive association with adenoma risk that we previously reported for circulating 27-OHC persisted controlling for the other oxysterols including 7ɑ-OHC (RR of any adenomas per SD circulating 27-OHC 1.07; 95% CI, 0.99-1.15 and RR of advanced adenomas, 1.23; 95% CI, 1.03-1.48). No statistically significant associations were observed for circulating 25-OHC, 24(S)-OHC, and 4β-OHC. We conclude that circulating 7ɑ-OHC and 27-OHC may be independently associated with colorectal adenoma risk. Given these two oxysterols are the initial products of the classic (neutral) and alternative (acidic) pathways for primary bile acid synthesis, respectively, our findings provide additional evidence in support of a role for bile acids in the development of colorectal neoplasia. Novel colorectal cancer prevention strategies may target oxysterol formation.

Citation Format: Michael N. Passarelli, Bonne M. Thompson, Jeffrey G. McDonald, Thomas J. Palys, Judy R. Rees, Elizabeth L. Barry, John A. Baron. Plasma concentrations of multiple oxysterols and risk of colorectal adenomas. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P009.