# Project 1: Oxysterols and colorectal adenomas: circulating concentrations and genotypes

> **NIH NIH P20** · DARTMOUTH COLLEGE · 2020 · $183,819

## Abstract

PROJECT 1 ABSTRACT
Colorectal cancer is the second leading cause of cancer-related death in the United States, by can be
prevented by the early detection of premalignant adenomatous polyps (adenomas). Individuals with large
adenomas with advanced pathology, sessile serrated adenomas, or multiple adenomas of any size are at
particularly increased risk of developing a subsequence colorectal cancer. Dyslipidemia and metabolic
syndrome are potential risk factors for colorectal neoplasia, but there is inconsistent evidence that blood
cholesterol concentrations or use of lipid-lowering drugs are associated with colorectal adenomas or cancer.
For this research project, we will focus on the first-step metabolism products of cholesterol in the biosynthesis
of bile acids, known as oxysterols, which are now detectable in human circulation at concentrations using
recent breakthrough in analytical chemistry. One of the most abundant circulating oxysterols, 27-
hydroxycholesterol (27-HC), has been shown in exhibit pro-inflammatory and pro-migratory properties in
preclinical studies. 27-HC has recently been found to function as a selective estrogen receptor modulator and
has been implicated in breast cancer development. Colorectal cancer also is susceptible to hormonal effects;
whereas use of exogenous estrogens increases the risk of breast cancer, estrogens tend to decrease the risk
of colorectal cancer. In addition to 27-HC, several other oxysterol species are known to promote apoptosis and
recruit inflammatory cytokines, including 25-hydroxycholesterol (25-HC), 7β-hydroxycholesterol (7-HC), and
4β-hydroxycholesterol (4-HC). We will test the association between plasma concentrations of theses
oxysterols and colorectal adenoma recurrence in the Vitamin D and Calcium Polyp Prevention Study, a
completed, multicenter, randomized, placebo-controlled, partial-factorial clinical trial of vitamin D and/or
calcium supplementation for the prevention of recurrent adenomas. In total, 1,622 men and women with
colorectal adenomas who received a follow-up colonoscopy up to 5 years after their initial polypectomy have
available fasting plasma and previously-collected germline genotype data. Oxysterols will be measured from
stored specimens using high-performance liquid chromatography-mass spectrometry. Secondarily, we will test
associations with 25-, 7-, and 4-HC, and explore sources of heterogeneity in the associations by adenoma
pathology and anatomic location of adenomas. We also plan to conduct two genetic association studies in
relation to adenoma recurrence, focusing on variants from: 1) candidate genes known to function in 27-HC
metabolism; and 2) a genome-wide scan to discover and replicate novel associations with circulating 27-HC
concentrations. Exploratory analyses will evaluate whether adenoma recurrence by 27-HC blood levels is
heterogeneous according to these genotypes. This first assessment of blood oxysterols in relation to colorectal
adenomas will contribute...

## Key facts

- **NIH application ID:** 9843720
- **Project number:** 5P20GM104416-08
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** Michael N Passarelli
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $183,819
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9843720

## Citation

> US National Institutes of Health, RePORTER application 9843720, Project 1: Oxysterols and colorectal adenomas: circulating concentrations and genotypes (5P20GM104416-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9843720. Licensed CC0.

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