Genome-wide DNA Methylation Profiling Identifies Epigenetic Signatures of Gastric Cardiac Intestinal Metaplasia

Overview

Journal J Transl Med

Publisher Biomed Central

Specialties Biomedical Engineering
General Medicine

Date 2020 Aug 2

PMID 32736574

Citations 8

Authors

Runhua Lin

Chenxi Li

Zhaohui Liu

Ruinuan Wu

Jianghong Lu

Affiliations

Soon will be listed here.

Abstract

Background: Measuring the DNA methylome may offer the opportunity to identify novel disease biomarkers and insights into disease mechanisms. Although aberrant DNA methylation has been investigated in many human cancers and precancerous lesions, the DNA methylation landscape of gastric cardiac intestinal metaplasia (IM) remains unknown. Therefore, we aimed to investigate the genome-wide DNA methylation landscape and to search for potential epigenetic biomarkers of gastric cardiac IM.

Methods: Histopathologic profiling was performed on a total of 118 gastric cardiac biopsies from cancer-free individuals. Genome-wide DNA methylation analysis was performed on 11 gastric cardiac mucosal biopsies (IM = 7; normal = 4) using Illumina 850K microarrays. Transcriptional relevance of any candidate epigenetic biomarker was validated by qRT-PCR.

Results: The detection rate of gastric cardiac IM was 23% (27/118) in cancer-free individuals. Genome-wide DNA methylation profiling showed a global decrease in methylation in IM compared with normal tissues (median methylation = 0.64 and 0.70 for gastric cardiac IM and normal tissues, respectively). Differential methylation analysis between gastric cardiac IM and normal tissues identified 38,237 differentially methylated probes (DMPs) with a majority of sites showing hypermethylation in IM compared with normal tissues (56.3% vs. 43.7%). Subsequent analysis revealed a significant enrichment of hypermethylated DMPs in promoter and CpG islands (p < 0.001 for both, Pearson χ test). For DMPs located in promoter CpG islands showing extreme hypermethylation, the candidate gene with the largest number of DMPs (n = 7) was mapped to HOXA5. Accordingly, mRNA expression of HOXA5 was significantly reduced in IM compared to normal tissue.

Conclusions: Our results suggest the implication of alterations in DNA methylation in gastric cardiac IM and highlight that HOXA5 hypermethylation may be a promising epigenetic biomarker, emphasizing the role of aberrant HOXA5 expression in the pathogenesis of gastric cardiac IM.

Citing Articles

Cellular plasticity and fate determination in gastric carcinogenesis.

He Z, Hu X, He T, Zhao T iScience. 2024; 27(4):109465.

PMID: 38550991 PMC: 10973593. DOI: 10.1016/j.isci.2024.109465.

Genome-wide DNA methylation pattern in whole blood of patients with Hashimoto thyroiditis.

Zhou Z, Liu J, Chen Y, Ren B, Wan S, Chen Y Front Endocrinol (Lausanne). 2023; 14:1259903.

PMID: 38075038 PMC: 10704911. DOI: 10.3389/fendo.2023.1259903.

Aberrant DNA methylation and expression of in gastric cardia intestinal metaplasia.

Li C, Liu Z, Xu G, Wu S, Peng Y, Wu R Saudi J Gastroenterol. 2022; 28(6):456-465.

PMID: 36453428 PMC: 9843510. DOI: 10.4103/sjg.sjg_228_22.

Integrated Analysis of Multi-Omics Data to Establish a Hypoxia-Related Prognostic Model in Osteosarcoma.

Tong Y, Zhang X, Zhou Y Evol Bioinform Online. 2022; 18:11769343221128537.

PMID: 36325183 PMC: 9618759. DOI: 10.1177/11769343221128537.

Kyoto international consensus report on anatomy, pathophysiology and clinical significance of the gastro-oesophageal junction.

Sugano K, Spechler S, El-Omar E, McColl K, Takubo K, Gotoda T Gut. 2022; 71(8):1488-1514.

PMID: 35725291 PMC: 9279854. DOI: 10.1136/gutjnl-2022-327281.

References

Huang K, Ramnarayanan K, Zhu F, Srivastava S, Xu C, Tan A . Genomic and Epigenomic Profiling of High-Risk Intestinal Metaplasia Reveals Molecular Determinants of Progression to Gastric Cancer. Cancer Cell. 2018; 33(1):137-150.e5. DOI: 10.1016/j.ccell.2017.11.018. View

Berman D, Karhadkar S, Maitra A, Montes de Oca R, Gerstenblith M, Briggs K . Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature. 2003; 425(6960):846-51. DOI: 10.1038/nature01972. View

Daugaard I, Dominguez D, Kjeldsen T, Kristensen L, Hager H, Wojdacz T . Identification and validation of candidate epigenetic biomarkers in lung adenocarcinoma. Sci Rep. 2016; 6:35807. PMC: 5080630. DOI: 10.1038/srep35807. View

Linehan W, Ricketts C . The Cancer Genome Atlas of renal cell carcinoma: findings and clinical implications. Nat Rev Urol. 2019; 16(9):539-552. DOI: 10.1038/s41585-019-0211-5. View

Strathdee G, Sim A, Soutar R, Holyoake T, Brown R . HOXA5 is targeted by cell-type-specific CpG island methylation in normal cells and during the development of acute myeloid leukaemia. Carcinogenesis. 2006; 28(2):299-309. DOI: 10.1093/carcin/bgl133. View

Vymetalkova V, Vodicka P, Pardini B, Rosa F, Levy M, Schneiderova M . Epigenome-wide analysis of DNA methylation reveals a rectal cancer-specific epigenomic signature. Epigenomics. 2016; 8(9):1193-207. DOI: 10.2217/epi-2016-0044. View

Xu E, Gu J, Hawk E, Wang K, Lai M, Huang M . Genome-wide methylation analysis shows similar patterns in Barrett's esophagus and esophageal adenocarcinoma. Carcinogenesis. 2013; 34(12):2750-6. PMC: 3845893. DOI: 10.1093/carcin/bgt286. View

Ordonez-Moran P, Dafflon C, Imajo M, Nishida E, Huelsken J . HOXA5 Counteracts Stem Cell Traits by Inhibiting Wnt Signaling in Colorectal Cancer. Cancer Cell. 2015; 28(6):815-829. DOI: 10.1016/j.ccell.2015.11.001. View

Yu M, OLeary R, Kaz A, Morris S, Carter K, Chak A . Methylated B3GAT2 and ZNF793 Are Potential Detection Biomarkers for Barrett's Esophagus. Cancer Epidemiol Biomarkers Prev. 2015; 24(12):1890-7. PMC: 4670566. DOI: 10.1158/1055-9965.EPI-15-0370. View

10.

Luo Y, Wong C, Kaz A, Dzieciatkowski S, Carter K, Morris S . Differences in DNA methylation signatures reveal multiple pathways of progression from adenoma to colorectal cancer. Gastroenterology. 2014; 147(2):418-29.e8. PMC: 4107146. DOI: 10.1053/j.gastro.2014.04.039. View

11.

Boucherat O, Montaron S, Berube-Simard F, Aubin J, Philippidou P, Wellik D . Partial functional redundancy between Hoxa5 and Hoxb5 paralog genes during lung morphogenesis. Am J Physiol Lung Cell Mol Physiol. 2013; 304(12):L817-30. PMC: 3680751. DOI: 10.1152/ajplung.00006.2013. View

12.

Smyth G . Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol. 2006; 3:Article3. DOI: 10.2202/1544-6115.1027. View

13.

Maksimovic J, Gordon L, Oshlack A . SWAN: Subset-quantile within array normalization for illumina infinium HumanMethylation450 BeadChips. Genome Biol. 2012; 13(6):R44. PMC: 3446316. DOI: 10.1186/gb-2012-13-6-r44. View

14.

Aryee M, Jaffe A, Corrada-Bravo H, Ladd-Acosta C, Feinberg A, Hansen K . Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays. Bioinformatics. 2014; 30(10):1363-9. PMC: 4016708. DOI: 10.1093/bioinformatics/btu049. View

15.

Chen H, Zhang H, Lee J, Liang X, Wu X, Zhu T . HOXA5 acts directly downstream of retinoic acid receptor beta and contributes to retinoic acid-induced apoptosis and growth inhibition. Cancer Res. 2007; 67(17):8007-13. DOI: 10.1158/0008-5472.CAN-07-1405. View

16.

Mikeska T, Bock C, Do H, Dobrovic A . DNA methylation biomarkers in cancer: progress towards clinical implementation. Expert Rev Mol Diagn. 2012; 12(5):473-87. DOI: 10.1586/erm.12.45. View

17.

Wrangle J, Machida E, Danilova L, Hulbert A, Franco N, Zhang W . Functional identification of cancer-specific methylation of CDO1, HOXA9, and TAC1 for the diagnosis of lung cancer. Clin Cancer Res. 2014; 20(7):1856-64. PMC: 4019442. DOI: 10.1158/1078-0432.CCR-13-2109. View

18.

Wu W, Bhagat T, Yang X, Song J, Cheng Y, Agarwal R . Hypomethylation of noncoding DNA regions and overexpression of the long noncoding RNA, AFAP1-AS1, in Barrett's esophagus and esophageal adenocarcinoma. Gastroenterology. 2013; 144(5):956-966.e4. PMC: 3739703. DOI: 10.1053/j.gastro.2013.01.019. View

19.

Sugimoto K, Ito T, Hulbert A, Chen C, Orita H, Maeda M . DNA methylation genome-wide analysis in remnant and primary gastric cancers. Gastric Cancer. 2019; 22(6):1109-1120. DOI: 10.1007/s10120-019-00949-5. View

20.

Boucherat O, Chakir J, Jeannotte L . The loss of Hoxa5 function promotes Notch-dependent goblet cell metaplasia in lung airways. Biol Open. 2012; 1(7):677-91. PMC: 3507293. DOI: 10.1242/bio.20121701. View