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5-hydroxymethylated biomarkers in cell-free DNA predict occult colorectal cancer up to 36 months prior to diagnosis in the PLCO Cancer Screening Trial

ABSTRACT: 5-hydroxymethylated biomarkers in cell-free DNA predict occult colorectal cancer up to 36 months prior to diagnosis in the PLCO Cancer Screening Trial

PROVIDER: PRJNA1095478 | ENA |

REPOSITORIES: ENA

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Project description:Purpose: Using the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial samples, we identified cell-free DNA (cfDNA) biomarker candidate genes bearing the epigenetic mark 5-hydroxymethylcytosine (5hmC) that detect occult colorectal cancer (CRC) up to 36 mo prior to clinical diagnosis. Methods: PLCO study subjects were matched by age, race, and sex as cases (n = 201, diagnosed with CRC within 36 mo of blood collection) and controls (n = 402, no cancer diagnosis on follow-up, average 16.3 years after entering the study). Archived plasma samples (300 µL per study subject) were obtained from the National Cancer Institute (NCI), and we employed the sensitive 5hmC-Seal chemical labeling approach on 3 - 8 ng of extracted cfDNA. Following next-generation sequencing (NGS) and genome-wide mapping of 5hmC, we then conducted association studies and machine-learning modeling to analyze the genome-wide 5hmC profiles within training and validation groups that were randomly selected at a 2:1 ratio. Results: Robust genome-wide 5hmC profiles were successfully obtained from these decades-old samples. Association analyses using the Cox proportional hazards models suggested several epigenetic pathways relevant to CRC development distinguishing cases from controls. A weighted Cox model, comprised of 32-associated gene bodies, showed predictive detection value for CRC as early as 24-36 mo prior to overt tumor diagnosis. Furthermore, a trend for increased predictive power was observed for blood samples collected closer to CRC diagnosis. Notably, the 5hmC-based predictive model showed comparable performance regardless of sex and self-reported race/ethnicity, and significantly outperformed risk factors such as age and obesity assessed as BMI (body mass index). Conclusion: An assay and machine learning modeling of 5hmC epigenetic signals on cfDNA revealed candidate biomarkers and a scoring algorithm with the potential to predict CRC occurrence despite the absence of clinical symptoms or the availability of effective predictors. Developing a minimally-invasive clinical assay that detects 5hmC-modified biomarkers holds promise for improving early CRC detection and ultimately patient outcomes. Future investigations to expand this strategy to prospectively collected samples are warranted.

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5-hydroxymethylated biomarkers in cell-free DNA predict occult colorectal cancer up to 36 months prior to diagnosis in the PLCO Cancer Screening Trial

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