An Eight-CpG-based Methylation Classifier for Preoperative Discriminating Early and Advanced-Late Stage of Colorectal Cancer

Ji Hu; Fu-Ying Zhao; Bin Huang; Jing Ran; Mei-Yuan Chen; Hai-Lin Liu; You-Song Deng; Xia Zhao; Xiao-Fan Han

doi:10.3389/fgene.2020.614160

An Eight-CpG-based Methylation Classifier for Preoperative Discriminating Early and Advanced-Late Stage of Colorectal Cancer

Front Genet. 2021 Jan 13:11:614160. doi: 10.3389/fgene.2020.614160. eCollection 2020.

Authors

Ji Hu¹, Fu-Ying Zhao², Bin Huang³, Jing Ran⁴, Mei-Yuan Chen¹, Hai-Lin Liu⁵, You-Song Deng¹, Xia Zhao⁶, Xiao-Fan Han¹

Affiliations

¹ Department of General Surgery, The First People's Hospital of Chongqing Liang Jiang New Area, Chongqing, China.
² Department of Medical Laboratory, The First People's Hospital of Chongqing Liang Jiang New Area, Chongqing, China.
³ Department of General Surgery, Daping Hospital, Army Medical University, Chongqing, China.
⁴ Department of Pathology, The First People's Hospital of Chongqing Liang Jiang New Area, Chongqing, China.
⁵ Department of Clinical Pharmacy, The First People's Hospital of Chongqing Liang Jiang New Area, Chongqing, China.
⁶ Department of Microbiology, Army Medical University, Chongqing, China.

Abstract

Aim: To develop and validate a CpG-based classifier for preoperative discrimination of early and advanced-late stage colorectal cancer (CRC).

Methods: We identified an epigenetic signature based on methylation status of multiple CpG sites (CpGs) from 372 subjects in The Cancer Genome Atlas (TCGA) CRC cohort, and an external cohort (GSE48684) with 64 subjects by LASSO regression algorithm. A classifier derived from the methylation signature was used to establish a multivariable logistic regression model to predict the advanced-late stage of CRC. A nomogram was further developed by incorporating the classifier and some independent clinical risk factors, and its performance was evaluated by discrimination and calibration analysis. The prognostic value of the classifier was determined by survival analysis. Furthermore, the diagnostic performance of several CpGs in the methylation signature was evaluated.

Results: The eight-CpG-based methylation signature discriminated early stage from advanced-late stage CRC, with a satisfactory AUC of more than 0.700 in both the training and validation sets. This methylation classifier was identified as an independent predictor for CRC staging. The nomogram showed favorable predictive power for preoperative staging, and the C-index reached 0.817 (95% CI: 0.753-0.881) and 0.817 (95% CI: 0.721-0.913) in another training set and validation set respectively, with good calibration. The patients stratified in the high-risk group by the methylation classifier had significantly worse survival outcome than those in the low-risk group. Combination diagnosis utilizing only four of the eight specific CpGs performed well, even in CRC patients with low CEA level or at early stage.

Conclusions: Our classifier is a valuable predictive indicator that can supplement established methods for more accurate preoperative staging and also provides prognostic information for CRC patients. Besides, the combination of multiple CpGs has a high value in the diagnosis of CRC.

Keywords: CpG site; DNA methylation; classifier; colorectal cancer; stage.