Wednesday, January 15, 2025
1/15/2025
PROJECT SUMMARY / ABSTRACT DNA methylation (DNAm) aberrancies are hallmarks of colorectal cancer (CRC) and substantially outnumber somatic mutations. So far, most DNAm studies have focused on CRC tissues. In contrast, DNAm changes in prediagnostic blood are poorly characterized in individuals with CRC but have great promise for early detection. Moreover, DNAm is potentially modifiable and thus represents one of the most promising targets for early interception of CRC. Therefore, we propose the largest prospective study to date to characterize the landscape of genome-wide DNAm markers associated with CRC and examine the biological role of blood DNAm in CRC. Our central hypothesis is that DNAm alterations in pre-diagnosis blood predict CRC risk, underlies the genetic effect on CRC susceptibility and tumor gene expression, and capture lifestyle-related changes in the aging and systemic immune pathways underlying CRC development. To address this hypothesis, we will leverage the genome-wide DNAm analysis supported by X01 HG012677 in pre-diagnosis white blood cells of 1,150 cases and 2,460 matched controls identified from 4 prospective cohorts of racially diverse men and women, including the Nurses’ Health Study (NHS), NHS2, Health Professionals Follow-up Study (HPFS), and Black Women’s Health Study (BWHS). Participants have provided diet/lifestyle data every 2-4 years over the past 20-40 years; ~80% of the cases and controls have been genotyped in prior genome-wide association studies; and a subset of them have also provided up to two blood samples 10 years apart (250 cases, 500 matched controls) and CRC tumor tissues with available RNA sequencing (n~250) and other molecular data (n~460). In Aim 1, we will characterize the landscape of genome-wide DNAm markers in pre-diagnosis blood associated with CRC incidence through an epigenome-wide association analysis and assess to what extent adding DNAm markers can improve the performance of established CRC risk assessment tools based on known epidemiologic risk factors. In Aim 2, we will integrate blood DNAm with germline genetics, DNAm quantitative trait loci, and tumor gene expression data to identify DNAm pathways underlying the genetic effect on CRC development and examine the association of blood DNAm with tumor gene expression. In Aim 3, we will prospectively examine epigenetic age acceleration (difference in epigenetic and chronological age) and DNAm- based estimates of circulating immune cell compositions in relation to CRC. We will also link epigenetic aging and immunity to tumoral molecular markers to inform biology. In addition, we will develop a diet/lifestyle score to characterize individuals’ potential of epigenetic aging and systemic immune modulatory capacity and associate this score with CRC risk. Taken together, with the support of the already approved X01, investigations of these aims in 4 large established cohorts provides a cost-efficient opportunity to prospectively characterize the role of DNAm in CRC onset and develop potential DNAm-based strategies for CRC risk stratification and prevention.
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