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Genetics and Genomics

Genome-wide methylation profiling identifies a novel gene signature for patients with synchronous colorectal cancer

British Journal of Cancer volume 128, pages 112–120 (2023)Cite this article

Subjects

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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Fig. 1: Identification of a methylation panel for the identification of patients with SyCRC.
Fig. 2: Establishment of a six-gene methylation signature using MethyLight qPCR assays in an independent clinical cohort.
Fig. 3: Comparison of methylation signatures between pairs of synchronous tumours.
Fig. 4: Prognostic potential of the methylation signature for the patients with SyCRC.

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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.

Author information

Author notes

  1. These authors contributed equally: Yasuyuki Okada, Fuduan Peng, Wei Li, Ajay Goel.

Authors and Affiliations

  1. Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Monrovia, CA, USA

    Yasuyuki Okada & Ajay Goel

  2. Department of Gastroenterology and Oncology, Tokushima University Graduate School, Tokushima, Japan

    Yasuyuki Okada

  3. Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA

    Fuduan Peng & Wei Li

  4. Molecular Medicine Unit. Department of Medicine, Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain

    José Perea

  5. Surgery Department, Vithas Arturo Soria University Hospital and School of Medicine, European University of Madrid, Madrid, Spain

    José Perea

  6. Hematology Department, University Hospital of Salamanca, Salamanca, Spain

    Luis Corchete

  7. Institute of Biomedical Research of Salamanca (IBSAL), Cancer Research Center (CiC-IBMCC, CSIC/USAL), Center for Biomedical Research in Network of Cancer (CIBERONC), Salamanca, Spain

    Luis Corchete

  8. Gastroenterology Department, Instituto Biodonostia, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Universidad del País Vasco (UPV/EHU), San Sebastián, Spain

    Luis Bujanda

  9. City of Hope Comprehensive Cancer Center, Duarte, CA, USA

    Ajay Goel

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Contributions

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.

Corresponding authors

Correspondence to Wei Li or Ajay Goel.

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The authors declare no competing interests.

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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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