Abstract
Background
There are no robust tools for the diagnosis of synchronous colorectal cancer (SyCRC). Herein, we developed the first methylation signature to identify and characterise patients with SyCRC.
Methods
For biomarker discovery, we analysed the genome-wide methylation profiles of 16 SyCRC and 18 solitary colorectal cancer (SoCRC) specimens. We thereafter established a methylation signature risk-scoring model to identify SyCRC in an independent cohort of 38 SyCRC and 42 SoCRC patients. In addition, we evaluated the prognostic value of the identified methylation profile.
Results
We identified six differentially methylated CpG probes/sites that distinguished SyCRC from SoCRC. In the validation cohort, we developed a methylation panel that identified patients with SyCRC from not only larger tumour (AUC = 0.91) but also the paired remaining tumour (AUC = 0.93). Moreover, high risk scores of our panel were associated with the development of metachronous CRC among patients with SyCRC (AUC = 0.87) and emerged as an independent predictor for relapse-free survival (hazard ratio = 2.72; 95% CI = 1.12–6.61). Furthermore, the risk stratification model which combined with clinical risk factors was a diagnostic predictor of recurrence (AUC = 0.90).
Conclusions
Our novel six-gene methylation panel robustly identifies patients with SyCRC, which has the clinical potential to improve the diagnosis and management of patients with CRC.
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Data availability
The data sets used for the current study are available from the corresponding author on reasonable request.
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Acknowledgements
We thank Tatsuhiko Kakisaka, Priyanka Sharma, Satoshi Nishiwada, Yuma Wada, In Seob Lee, Geeta Sharma, Divya Sahu, Xiao Zhang, Yinghui Zhao, and Yuetong Chen for helping to conduct the experiments and data analysis. We also would like to extend our thanks to Dr. Kerin Higa for her significant editing and useful suggestions for improving the quality of our manuscript.
Funding
This work was supported by CA72851, CA181572, CA184792, CA202797, and CA227602 grants from the National Cancer Institute, National Institutes of Health.
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YO: study concept and design; analysis and interpretation of data and statistical analysis; drafting of the manuscript. FP: analysis and interpretation of data, statistical analysis; drafting of the manuscript. JP: specimen provider; acquisition of clinical data; drafting of the manuscript. LC: specimen provider; acquisition of clinical data; drafting of the manuscript. LB: specimen provider; acquisition of clinical data; drafting of the manuscript. WL: analysis and interpretation of data, statistical analysis; drafting of the manuscript. AG: study concept and design, analysis and interpretation of data, statistical analysis, drafting of the manuscript. All authors read and approved the final manuscript.
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The study was conducted in accordance with the Declaration of Helsinki. A written informed consent was obtained from all patients, and the study was approved by the institutional review boards of the participating institutions.
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Okada, Y., Peng, F., Perea, J. et al. Genome-wide methylation profiling identifies a novel gene signature for patients with synchronous colorectal cancer. Br J Cancer 128, 112–120 (2023). https://doi.org/10.1038/s41416-022-02033-9
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DOI: https://doi.org/10.1038/s41416-022-02033-9