Abstract
PURPOSE Using the prostate, lung, colorectal, and ovarian (PLCO) Cancer Screening Trial samples, we identified cell-free DNA (cfDNA) candidate biomarkers bearing the epigenetic mark 5-hydroxymethylcytosine (5hmC) that detected occult colorectal cancer (CRC) up to 36 months before clinical diagnosis. MATERIALS We performed the 5hmC-seal assay and sequencing on ≤8 ng cfDNA extracted AND METHODS from PLCO study participant plasma samples, including n 5 201 cases (diagnosed with CRC within 36 months of blood collection) and n 5 401 controls (no cancer diagnosis on follow-up). We 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 We successfully obtained 5hmC profiles from these decades-old samples. A weighted Cox model of 32 5hmC-modified gene bodies showed a predictive detection value for CRC as early as 36 months before overt tumor diagnosis (training set AUC, 77.1% [95% CI, 72.2 to 81.9] and validation set AUC, 72.8% [95% CI, 65.8 to 79.7]). Notably, the 5hmC-based predictive model showed comparable performance regardless of sex and race/ethnicity, and significantly outperformed risk factors such as age and obesity (assessed as BMI). Finally, when splitting cases at median weighted prediction scores, Kaplan-Meier analyses showed significant risk stratification for CRC occurrence in both the training set (hazard ratio, [HR], 3.3 [95% CI, 2.6 to 5.8]) and validation set (HR, 3.1 [95% CI, 1.8 to 5.8]). CONCLUSION Candidate 5hmC biomarkers and a scoring algorithm have the potential to predict CRC occurrence despite the absence of clinical symptoms and effective predictors. Developing a minimally invasive clinical assay that detects 5hmC-modified biomarkers holds promise for improving early CRC detection and ultimately patient outcomes.
| Original language | English (US) |
|---|---|
| Article number | e2400277 |
| Journal | JCO Precision Oncology |
| Volume | 8 |
| DOIs | |
| State | Published - Oct 1 2024 |
Funding
Supported in part by the NCI (U01CA217078). This work was partially supported by the Institute for Translational Medicine and the Chicago Biomedical Consortium. Chuan He is an investigator of the Howard Hughes Medical Institute. The authors thank the NCI for access to the data collected by the PLCO Trial. The authors would like to acknowledge the valuable contributions of Mr Matthew Moore of Information Management Services, who sadly passed away before the manuscript was accepted for publication. Mr Moore assisted with the selecting of patients with PLCO cancer and controls who met inclusion and exclusion criteria, and arranging the transfer of the PLCO samples. It was the authors\u2019 intention to list Mr Moore as a coauthor of this work; however, because of procedural requirements related to financial disclosures that could not be completed posthumously, we respectfully include his name in the Acknowledgment section instead.
ASJC Scopus subject areas
- Oncology
- Cancer Research
