Abstract 1009: DNA methylation-predicted plasma proteins and risk of colorectal cancer recurrence: Findings from the ColoCare Study

Abstract Introduction: DNA methylation (DNAm)-based predictors of individual proteins (e.g., C-reactive Protein, Interleukin-6) show better predictive performance for various health outcomes compared to direct measurements. This improved performance may be due to the higher reliability and temporal stability of DNAm profiles than direct protein measurements. Building on these findings, a library of 109 DNAm-predicted plasma proteins, called “Protein EpiScores, ” was developed using paired plasma proteomic and blood DNAm data from thousands of individuals. Initial studies of Protein EpiScores identified associations with CRC risk, suggesting their potential as novel biomarkers for CRC prediction and as indicators of mechanisms underlying CRC development. Here, we extend the investigation of Protein EpiScores to cancer survivorship by investigating their associations with risk of recurrence and all-cause mortality in newly diagnosed CRC patients. Methods: The ColoCare Study is an international, multi-center, prospective cohort of newly diagnosed CRC patients. For this study, we selected a nested case-control sample of 137 patients enrolled at Moffitt Cancer Center, matching recurrence cases 1:3 to recurrence-free controls by age, sex, body mass index, stage, and follow-up time. Pre-treatment whole blood DNA methylation profiles were assayed and used to calculate 109 Protein EpiScores. Logistic regression models, adjusted for matching factors and tumor location, estimated odds ratios (ORs) for associations between each Protein EpiScore (per 1-standard deviation [SD] increase) and risks of CRC recurrence and all-cause mortality. Results: Patients had a mean age of 62.7 years at diagnosis (SD= 13), with a majority being male (57%), overweight (78%), and White (90%). During follow-up, 35 (25%) patients experienced disease recurrence, and 47 (34%) died. Sixteen Protein EpiScores were associated with CRC recurrence risk (HRs ranging from 0.55 to 1.88; all P< 0.05). These included six Protein EpiScores designed to predict proteins related to immune response and inflammation (CCL11, PIGR, CCL17, MMP12, OSM, PAPPA), with all showing positive associations except for PAPPA. Ten Protein EpiScores were positively associated with all-cause mortality (all P< 0.05), including five immune response and inflammation Protein EpiScores (OSM, S100A12, CCL22, PIGR, S100A9). Conclusions: Multiple Protein EpiScores measured in pre-treatment blood samples were associated with CRC recurrence risk and mortality. Many of these Protein EpiScores were designed to predict proteins involved in immune response and inflammation, suggesting that changes in peripheral immunity contribute to disease progression. Citation Format: Alicia Richards, Esther Jean-Baptiste, Timothy Barrow, Sheetal Hardikar, Biljana Gigic, Jane Figueiredo, Christopher Li, David Shibata, Adetunji T. Toriola, Doratha A. Byrd, Cornelia M. Ulrich, Paul Stewart, Erin M. Siegel, Jacob K. Kresovich. DNA methylation-predicted plasma proteins and risk of colorectal cancer recurrence: Findings from the ColoCare Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1009.