Abstract
AimTo develop and validate a CpG-based classifier for preoperative discrimination of early and advanced-late stage colorectal cancer (CRC).MethodsWe 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.ResultsThe 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.ConclusionsOur 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.
Highlights
Colorectal cancer (CRC) is one of the most common malignancies, and ranks third in terms of both incidence and mortality rates
A total of 372 CRC samples with well-defined pathological stages and 45 normal samples from TCGA cohort, and 64 CRC specimens with detailed stage information and 41 controls from the GEO cohort were included after applying the exclusion criteria
The TGCA CRC samples were randomly divided into the training set I (n = 260) and test set I (n = 112), and the GEO CRC cases were used as the validation set I (n = 64) as detailed in the methods
Summary
Colorectal cancer (CRC) is one of the most common malignancies, and ranks third in terms of both incidence and mortality rates. Tumor node metastases (TNM) staging is currently the “gold standard” for tumor classification, and accurate diagnosis of the tumor stage provides valuable prognostic information for guiding treatment decisions (De Rosa et al, 2016). Preoperative lymph node status assessment and prediction contain instructive information for the surgical extent between stage I/II and stage III cases (lymphnode positive) (Hashiguchi et al, 2020). Postoperative adjuvant chemotherapy is recommended for all stage III CRC without contraindications after curative resection (Brenner et al, 2014). Except for adjuvant chemotherapy, preoperative neoadjuvant therapy, surgical resection and targeted therapies should be taken into consideration according to multidisciplinary team decisions for stage IV CRC (Diagnosis And Treatment Guidelines For Colorectal Cancer Working Group Csococ, 2019). It is essential to develop a reliable and efficient tool for preoperative CRC staging in order to devise the optimum personalized therapeutic strategy (De Rosa et al, 2016)
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