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Genome-wide methylation profiling identified novel differentially hypermethylated biomarker MPPED2 in colorectal cancer

BACKGROUND: Epigenetic alternation is a common contributing factor to neoplastic transformation. Although previous studies have reported a cluster of aberrant promoter methylation changes associated with silencing of tumor suppressor genes, little is known concerning their sequential DNA methylation...

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Autores principales: Gu, Simeng, Lin, Shujuan, Ye, Ding, Qian, Sangni, Jiang, Danjie, Zhang, Xiaocong, Li, Qilong, Yang, Jinhua, Ying, Xiaojiang, Li, Zhenjun, Tang, Mengling, Wang, Jianbing, Jin, Mingjuan, Chen, Kun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407227/
https://www.ncbi.nlm.nih.gov/pubmed/30846004
http://dx.doi.org/10.1186/s13148-019-0628-y
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author Gu, Simeng
Lin, Shujuan
Ye, Ding
Qian, Sangni
Jiang, Danjie
Zhang, Xiaocong
Li, Qilong
Yang, Jinhua
Ying, Xiaojiang
Li, Zhenjun
Tang, Mengling
Wang, Jianbing
Jin, Mingjuan
Chen, Kun
author_facet Gu, Simeng
Lin, Shujuan
Ye, Ding
Qian, Sangni
Jiang, Danjie
Zhang, Xiaocong
Li, Qilong
Yang, Jinhua
Ying, Xiaojiang
Li, Zhenjun
Tang, Mengling
Wang, Jianbing
Jin, Mingjuan
Chen, Kun
author_sort Gu, Simeng
collection PubMed
description BACKGROUND: Epigenetic alternation is a common contributing factor to neoplastic transformation. Although previous studies have reported a cluster of aberrant promoter methylation changes associated with silencing of tumor suppressor genes, little is known concerning their sequential DNA methylation changes during the carcinogenetic process. The aim of the present study was to address a genome-wide search for identifying potentially important methylated changes and investigate the onset and pattern of methylation changes during the progression of colorectal neoplasia. METHODS: A three-phase design was employed in this study. In the screening phase, DNA methylation profile of 12 pairs of colorectal cancer (CRC) and adjacent normal tissues was analyzed by using the Illumina MethylationEPIC BeadChip. Significant CpG sites were selected based on a cross-validation analysis from The Cancer Genome Atlas (TCGA) database. Methylation levels of candidate CpGs were assessed using pyrosequencing in the training dataset (tumor lesions and adjacent normal tissues from 46 CRCs) and the validation dataset (tumor lesions and paired normal tissues from 13 hyperplastic polyps, 129 adenomas, and 256 CRCs). A linear mixed-effects model was used to examine the incremental changes of DNA methylation during the progression of colorectal neoplasia. RESULTS: The comparisons between normal and tumor samples in the screening phase revealed an extensive CRC-specific methylomic pattern with 174,006 (21%) methylated CpG sites, of which 22,232 (13%) were hyermethylated and 151,774 (87%) were hypomethylated. Hypermethylation mostly occurred in CpG islands with an overlap of gene promoters, while hypomethylation tended to be mapped far away from functional regions. Further cross validation analysis from TCGA dataset confirmed 265 hypermethylated promoters coupling with downregulated gene expression. Among which, hypermethylated changes in MEEPD2 promoter was successfully replicated in both training and validation phase. Significant hypermethylation appeared since precursor lesions with an extensive modification in CRCs. The linear mixed-effects modeling analysis found that a cumulative pattern of MPPED2 methylation changes from normal mucosa to hyperplastic polyp to adenoma, and to carcinoma (P < 0.001). CONCLUSIONS: Our findings indicate that epigenetic alterations of MPPED2 promoter region appear sequentially during the colorectal neoplastic progression. It might be able to serve as a promising biomarker for early diagnosis and stage surveillance of colorectal tumorigenesis. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13148-019-0628-y) contains supplementary material, which is available to authorized users.
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spelling pubmed-64072272019-03-21 Genome-wide methylation profiling identified novel differentially hypermethylated biomarker MPPED2 in colorectal cancer Gu, Simeng Lin, Shujuan Ye, Ding Qian, Sangni Jiang, Danjie Zhang, Xiaocong Li, Qilong Yang, Jinhua Ying, Xiaojiang Li, Zhenjun Tang, Mengling Wang, Jianbing Jin, Mingjuan Chen, Kun Clin Epigenetics Research BACKGROUND: Epigenetic alternation is a common contributing factor to neoplastic transformation. Although previous studies have reported a cluster of aberrant promoter methylation changes associated with silencing of tumor suppressor genes, little is known concerning their sequential DNA methylation changes during the carcinogenetic process. The aim of the present study was to address a genome-wide search for identifying potentially important methylated changes and investigate the onset and pattern of methylation changes during the progression of colorectal neoplasia. METHODS: A three-phase design was employed in this study. In the screening phase, DNA methylation profile of 12 pairs of colorectal cancer (CRC) and adjacent normal tissues was analyzed by using the Illumina MethylationEPIC BeadChip. Significant CpG sites were selected based on a cross-validation analysis from The Cancer Genome Atlas (TCGA) database. Methylation levels of candidate CpGs were assessed using pyrosequencing in the training dataset (tumor lesions and adjacent normal tissues from 46 CRCs) and the validation dataset (tumor lesions and paired normal tissues from 13 hyperplastic polyps, 129 adenomas, and 256 CRCs). A linear mixed-effects model was used to examine the incremental changes of DNA methylation during the progression of colorectal neoplasia. RESULTS: The comparisons between normal and tumor samples in the screening phase revealed an extensive CRC-specific methylomic pattern with 174,006 (21%) methylated CpG sites, of which 22,232 (13%) were hyermethylated and 151,774 (87%) were hypomethylated. Hypermethylation mostly occurred in CpG islands with an overlap of gene promoters, while hypomethylation tended to be mapped far away from functional regions. Further cross validation analysis from TCGA dataset confirmed 265 hypermethylated promoters coupling with downregulated gene expression. Among which, hypermethylated changes in MEEPD2 promoter was successfully replicated in both training and validation phase. Significant hypermethylation appeared since precursor lesions with an extensive modification in CRCs. The linear mixed-effects modeling analysis found that a cumulative pattern of MPPED2 methylation changes from normal mucosa to hyperplastic polyp to adenoma, and to carcinoma (P < 0.001). CONCLUSIONS: Our findings indicate that epigenetic alterations of MPPED2 promoter region appear sequentially during the colorectal neoplastic progression. It might be able to serve as a promising biomarker for early diagnosis and stage surveillance of colorectal tumorigenesis. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13148-019-0628-y) contains supplementary material, which is available to authorized users. BioMed Central 2019-03-07 /pmc/articles/PMC6407227/ /pubmed/30846004 http://dx.doi.org/10.1186/s13148-019-0628-y Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Gu, Simeng
Lin, Shujuan
Ye, Ding
Qian, Sangni
Jiang, Danjie
Zhang, Xiaocong
Li, Qilong
Yang, Jinhua
Ying, Xiaojiang
Li, Zhenjun
Tang, Mengling
Wang, Jianbing
Jin, Mingjuan
Chen, Kun
Genome-wide methylation profiling identified novel differentially hypermethylated biomarker MPPED2 in colorectal cancer
title Genome-wide methylation profiling identified novel differentially hypermethylated biomarker MPPED2 in colorectal cancer
title_full Genome-wide methylation profiling identified novel differentially hypermethylated biomarker MPPED2 in colorectal cancer
title_fullStr Genome-wide methylation profiling identified novel differentially hypermethylated biomarker MPPED2 in colorectal cancer
title_full_unstemmed Genome-wide methylation profiling identified novel differentially hypermethylated biomarker MPPED2 in colorectal cancer
title_short Genome-wide methylation profiling identified novel differentially hypermethylated biomarker MPPED2 in colorectal cancer
title_sort genome-wide methylation profiling identified novel differentially hypermethylated biomarker mpped2 in colorectal cancer
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407227/
https://www.ncbi.nlm.nih.gov/pubmed/30846004
http://dx.doi.org/10.1186/s13148-019-0628-y
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