Multiple gene promoter methylation and clinical stage in adjacent normal tissues: Effect on prognosis of colorectal cancer in Taiwan

Chih-Hsiung Hsu,Tsan Yang,Wen-Chih Wu,Yu-Chan Liao,Fu-Huang Lin,Chi-Hua Huang,Chao-Yang Chen,Yu-Ching Chou,Je-Ming Hu,Cheng-Wen Hsiao,Chien-An Sun

doi:10.1038/s41598-019-56691-6

Abstract

This study provide an insight that the panel genes methylation status in different clinical stage tended to reflect a different prognosis even in matched normal tissues, to clinical recommendation. We enrolled 153 colorectal cancer patients from a medical center in Taiwan and used the candidate gene approach to select five genes involved in carcinogenesis pathways. We analyzed the relationship between DNA methylation with different cancer stages and the prognostic outcome. There were significant trends of increasing risk of 5-year time to progression and event-free survival of subjects with raising number of hypermethylation genes both in normal tissue and tumor tissue. The group with two or more genes with aberrant methylation in the advanced cancer stages (Me/advanced) had lower 5-year event-free survival among patients with colorectal cancer in either normal or tumor tissue. The adjusted hazard ratios in the group with two or more genes with aberrant methylation with advanced cancer stages (Me/advanced) were 8.04 (95% CI, 2.80–23.1; P for trend <0.01) and 8.01 (95% CI, 1.92–33.4; P for trend <0.01) in normal and tumor tissue, respectively. DNA methylation status was significantly associated with poor prognosis outcome. This finding in the matched normal tissues of colorectal cancer patients could be an alternative source of prognostic markers to assist clinical decision making.

Highlights

This study provide an insight that the panel genes methylation status in different clinical stage tended to reflect a different prognosis even in matched normal tissues, to clinical recommendation
On the basis of the tumor and matched normal tissues of the patients, we classified the patient characteristics according to five individual gene groups (CDKN2A, human mutL homolog 1 (hMLH1), methylguanine DNA methyltransferase (MGMT), colony stimulating factor 2 (CSF2), and DIS3L2) and according to those with two or more genes with aberrant methylation, stratified by different variables
We analyzed and tested the prognostic outcome, including Time to progression (TTP), Overall survival (OS), and Event-free survival (EFS), in patients with Colorectal cancer (CRC) and found that the presence of hypermethylated DNA in the normal tissues could be predictive of worse outcomes in terms of TTP, OS, and EFS

Summary

Introduction

This study provide an insight that the panel genes methylation status in different clinical stage tended to reflect a different prognosis even in matched normal tissues, to clinical recommendation. DNA methylation status was significantly associated with poor prognosis outcome This finding in the matched normal tissues of colorectal cancer patients could be an alternative source of prognostic markers to assist clinical decision making. Previous studies have demonstrated that aberrant DNA methylation, the most frequent aberrant epigenetic modification in cancer, is an important www.nature.com/scientificreports early biomarker in CRC that is related to transcriptional silencing of tumor suppressor genes and a marker for field cancerization[9,10,11]. With these biomarkers, patients in the same tumor stage could be stratified by different individual molecular factors. We provide insight that the selected genes methylation status in different clinical stages tended to reflect a different prognosis, even in matched normal tissues, to clinical recommendations

Methods

Results

Conclusion