Using Comorbidity Pattern Analysis to Detect Reliable Methylated Genes in Colorectal Cancer Verified by Stool DNA Test.

Jhen-Li Huang,Cing-Han Yang,Pi-Kai Chang,Hsin-Hui Huang,Yi-Hsuan Tsai,Tun-Wen Pai,Shu-Wen Jao,Po-Hsien Wu,Yen-Ju Chen,Chia-Cheng Wen,Yu-Ching Chou,Yi-Chiao Cheng

doi:10.3390/genes12101539

Abstract

Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide in 2020. Colonoscopy and the fecal immunochemical test (FIT) are commonly used as CRC screening tests, but both types of tests possess different limitations. Recently, liquid biopsy-based DNA methylation test has become a powerful tool for cancer screening, and the detection of abnormal DNA methylation in stool specimens is considered as an effective approach for CRC screening. The aim of this study was to develop a novel approach in biomarker selection based on integrating primary biomarkers from genome-wide methylation profiles and secondary biomarkers from CRC comorbidity analytics. A total of 125 differential methylated probes (DMPs) were identified as primary biomarkers from 352 genome-wide methylation profiles. Among them, 51 biomarkers, including 48 hypermethylated DMPs and 3 hypomethylated DMPs, were considered as suitable DMP candidates for CRC screening tests. After comparing with commercial kits, three genes (ADHFE1, SDC2, and PPP2R5C) were selected as candidate epigenetic biomarkers for CRC screening tests. Methylation levels of these three biomarkers were significantly higher for patients with CRC than normal subjects. The sensitivity and specificity of integrating methylated ADHFE1, SDC2, and PPP2R5C for CRC detection achieved 84.6% and 92.3%, respectively. Through an integrated approach using genome-wide DNA methylation profiles and electronic medical records, we could design a biomarker panel that allows for early and accurate noninvasive detection of CRC using stool samples.

Highlights

Colorectal cancer (CRC) was the third most commonly diagnosed cancer and the second leading cause of cancer-related death worldwide in 2020 [1]
DNA methylation profiles of 314 patients pathologically diagnosed with CRC were compared with those of 38 normal subjects for identifying primary differential methylated probes (DMPs) biomarkers
The present study showed that a stool DNA methylation test could facilitate early detection of CRC and adenoma

Summary

Introduction

Colorectal cancer (CRC) was the third most commonly diagnosed cancer and the second leading cause of cancer-related death worldwide in 2020 [1]. The fecal immunochemical test (FIT) is the most commonly used screening method worldwide [5] because it is noninvasive and more economical, can be performed at home, and does not require bowel preparation. In studies using colonoscopy as a reference standard, the sensitivity of FITs for detecting invasive cancer and precancerous lesions only ranged from 65.8% to 75.0% and from 27.0% to 29.0%, respectively [6,7,8,9,10]. The FIT shows a worse performance for the detection of right-sided advanced adenomas than left-sided lesions [11]

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