Gastrointestinal adenocarcinoma analysis identifies promoter methylation-based cancer subtypes and signatures

Renshen Xiang,Tao Fu

doi:10.1038/s41598-020-78228-y

Renshen Xiang, Tao Fu

Open Access

https://doi.org/10.1038/s41598-020-78228-y

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Abstract

Gastric adenocarcinoma (GAC) and colon adenocarcinoma (CAC) are the most common gastrointestinal cancer subtypes, with a high incidence and mortality. Numerous studies have shown that its occurrence and progression are significantly related to abnormal DNA methylation, especially CpG island methylation. However, little is known about the application of DNA methylation in GAC and CAC. The methylation profiles were accessed from the Cancer Genome Atlas database to identify promoter methylation-based cancer subtypes and signatures for GAC and CAC. Six hypo-methylated clusters for GAC and six hyper-methylated clusters for CAC were separately generated with different OS profiles, tumor progression became worse as the methylation level decreased in GAC or increased in CAC, and hypomethylation in GAC and hypermethylation in CAC were negatively correlated with microsatellite instability. Additionally, the hypo- and hyper-methylated site-based signatures with high accuracy, high efficiency and strong independence can separately predict the OS of GAC and CAC patients. By integrating the methylation-based signatures with prognosis-related clinicopathologic characteristics, two clinicopathologic-epigenetic nomograms were cautiously established with strong predictive performance and high accuracy. Our research indicates that methylation mechanisms differ between GAC and CAC, and provides novel clinical biomarkers for the diagnosis and treatment of GAC and CAC.

Highlights

Gastric adenocarcinoma (GAC) and colon adenocarcinoma (CAC) are the most common gastrointestinal cancer subtypes, with a high incidence and mortality
Multivariate analysis revealed a total of 131 independent prognostic methylation sites [68 for GAC (Supplementary Table 1) and 63 for CAC (Supplementary Table 2)], which were used to identify GAC and CAC subtypes
According to promoter methylation-based consensus clustering, six clusters that contained all the GAC samples were identified at a clustering threshold of maxK = 6 (Fig. 2A–C)

Summary

Introduction

Gastric adenocarcinoma (GAC) and colon adenocarcinoma (CAC) are the most common gastrointestinal cancer subtypes, with a high incidence and mortality. The hypo- and hyper-methylated site-based signatures with high accuracy, high efficiency and strong independence can separately predict the OS of GAC and CAC patients. Abnormal DNA methylation, which is closely related to tumorigenesis and progression via the regulation of tumor suppressor genes, is the most thoroughly studied epigenetic m odification[10]. Several markers for overall survival (OS) of patients with gastrointestinal cancer have been developed according to transcription and methylation profiles, but these studies were based mostly on analysis of candidate genes and focused mainly on CpG island methylation and its relationship with gene e xpression[14,15,16,17,18]. The DNA methylation-based cancer subtypes and prognostic signatures for gastrointestinal adenocarcinoma have not been fully investigated

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