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Clinical Studies

A DNA methylation signature for the prediction of tumour recurrence in stage II colorectal cancer

British Journal of Cancer volume 128, pages 1681–1689 (2023)Cite this article

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Abstract

Background

A major challenge in stage II colorectal carcinoma is to identify patients with increased risk of recurrence. Biomarkers that distinguish patients with poor prognosis from patients without recurrence are currently lacking. This study aims to develop a robust DNA methylation classifier that allows the prediction of recurrence and chemotherapy benefit in patients with stage II colorectal cancer. We performed a genome-wide DNA methylation capture sequencing in 243 stage II colorectal carcinoma samples and identified a relapse-specific DNA methylation signature consisting of eight CpG sites.

Methods

Two hundred and forty-three patients with stage II CRC were enrolled in this study. In order to select differential methylation sites among recurrence and non-recurrence stage II CRC samples, DNA methylation profiles of 62 tumour samples including 31 recurrence and 31 nonrecurrence samples were analysed using the Agilent SureSelectXT Human Methyl-Seq, a comprehensive target enrichment system to analyse CpG methylation. Pyrosequencing was applied to quantify the methylation level of candidate DNA methylation sites in 243 patients. Least absolute shrinkage and selection operator (LASSO) method was employed to build the disease recurrence prediction classifier.

Results

We identified a relapse-related DNA methylation signature consisting of eight CpG sites in stage II CRC by DNA methylation capture sequencing. The classifier showed significantly higher prognostic accuracy than any clinicopathological risk factors. The Kaplan–Meier survival curve showed an association of high-risk score with poor prognosis. In multivariate analysis, the signature was the most significant prognosis factor, with an HR of 2.80 (95% CI, 1.71–4.58, P < 0.001). The signature could identify patients who are suitable candidates for adjuvant chemotherapy.

Conclusions

An eight-CpG DNA methylation signature is a reliable prognostic and predictive tool for disease recurrence in patients with stage II CRC.

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Fig. 1: Study flowchart.
Fig. 2: CpG methylation sites are significantly associated with recurrence in stage II CRC.
Fig. 3: DNA methylation signature is a biomarker for recurrence in stage II CRC.
Fig. 4: Association between the DNA methylation classifier and prognosis.
Fig. 5: DNA methylation signature is an independent prognostic factor in stage II CRC.
Fig. 6: DNA methylation classifier is more accurate in the prediction of disease recurrence and disease-free survival than other clinicopathological risk factors.

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Data availability

The data that support the findings of this study are available upon request from the corresponding authors.

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Funding

This study was supported by Ministry of Science and Technology of China (2021YFA0804700) (QH), National Natural Science Foundation of China (82072914, 81872358) (QH), National Key Research and Development Program of China (2020YFC2008400) (CM), and The Science and Technology Commission of Shanghai Municipality (20DZ1100101) (YX).

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Author notes

  1. These authors contributed equally: Min Li, Congcong Zhu, Ying Xue.

Authors and Affiliations

  1. Cancer Center, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032, Shanghai, P. R. China

    Min Li, Ying Xue, Changhong Miao, Ruiping He & Qihong Huang

  2. Institute of Clinical Sciences, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032, Shanghai, P. R. China

    Min Li, Ying Xue, Ruiping He, Minzhi Lv & Qihong Huang

  3. Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong’An Road, 200032, Shanghai, P. R. China

    Congcong Zhu & Ye Xu

  4. Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong’An Road, 200032, Shanghai, P. R. China

    Congcong Zhu & Ye Xu

  5. Department of Anesthesiology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032, Shanghai, P. R. China

    Changhong Miao

  6. Laboratory of RNA Epigenetics, Institute of Biomedical Sciences, Fudan University, 130 Dong’An Road, 200032, Shanghai, P. R. China

    Wei Li, Baolong Zhang & Wenqiang Yu

  7. School of Life Science and Technology, ShanghaiTech University, 201210, Shanghai, P. R. China

    Xingxu Huang

  8. Department of Biostatistics, Clinical Research Unit, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032, Shanghai, P. R. China

    Minzhi Lv

  9. Shanghai Respiratory Research Institute, 180 Fenglin Road, 200032, Shanghai, P. R. China

    Qihong Huang

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  1. Min Li
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Contributions

M Li: data curation, formal analysis, methodology, validation, writing; CZ: data curation, formal analysis; YX: data curation, formal analysis; CM: funding acquisition, resources; RH: data curation; WL: data curation; BZ: data curation; WY: funding acquisition, resources; XH: funding acquisition, resources; M Lv: formal analysis, validation, writing—original draft, writing—review and editing; YX: conceptualisation, formal analysis, funding acquisition, resources, supervision, writing—review and editing; QH: conceptualisation, formal analysis, funding acquisition, resources, supervision, writing—original draft, writing—review and editing.

Corresponding authors

Correspondence to Minzhi Lv, Ye Xu or Qihong Huang.

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This study was approved by the Institutional Review Board of the Fudan University Shanghai Cancer Center. All included patients gave their written consent to participate in this study.

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Li, M., Zhu, C., Xue, Y. et al. A DNA methylation signature for the prediction of tumour recurrence in stage II colorectal cancer. Br J Cancer 128, 1681–1689 (2023). https://doi.org/10.1038/s41416-023-02155-8

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