Abstract
Epigenetic mechanisms such as aberrant DNA methylation (DNAme) are known to drive esophageal squamous cell carcinoma (ESCC), yet they remain poorly understood. Here, we studied tumorspecific DNAme in ESCC cases from nine high-incidence countries of Africa, Asia, and SouthAmerica. Infinium MethylationEPIC array was performed on 108 tumors and 51 normal tissues adjacent to the tumors (NAT) in the discovery phase, and targeted pyrosequencing was performed on 132 tumors and 36 NAT in the replication phase. Top genes for replication were prioritized by weighting methylation results using RNA-sequencing data from The Cancer Genome Atlas and GTEx and validated by qPCR. Methylome analysis comparing tumor and NAT identified 6,796 differentially methylated positions (DMP) and 866 differential methylated regions (DMR), with a 30% methylation (Db) difference. The majority of identified DMPs and DMRs were hypermethylated in tumors, particularly in promoters and gene-body regions of genes involved in transcription activation. The top three prioritized genes for replication, PAX9, SIM2, and THSD4, had similar methylation differences in the discovery and replication sets. These genes were exclusively expressed in normal esophageal tissues in GTEx and downregulated in tumors. The specificity and sensitivity of these DNAme events in discriminating tumors from NAT were assessed. Our study identified novel, robust, and crucial tumor-specific DNAme events in ESCC tumors across several high-incidence populations of the world. Methylome changes identified in this study may serve as potential targets for biomarker discovery and warrant further functional characterization.
| Original language | English |
|---|---|
| Pages (from-to) | 2612-2624 |
| Number of pages | 13 |
| Journal | Cancer Research |
| Volume | 81 |
| Issue number | 10 |
| Early online date | 19 Mar 2021 |
| DOIs | |
| Publication status | Published - May 2021 |
| Externally published | Yes |
Bibliographical note
Funding Information:S.C. Soares Lima reports grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico and Fundac¸ão de Amparo à Pesquisa do Estado do Rio de Janeiro—FAPERJ during the conduct of the study. M.L. Roux reports grants from American Cancer Society during the conduct of the study. No disclosures were reported by the other authors.
Funding Information:
The work reported in this article was undertaken by F.R. Talukdar partly during the tenure of a Postdoctoral Fellowship from the International Agency for Research on Cancer (IARC), partially supported by the EC FP7 Marie Curie Actions—People— Co-funding of regional, national, and international programs (COFUND). The work in the Epigenetics Group at IARC is supported by grants from the Institut National du Cancer (INCa, France), the European Commission (EC) Seventh Framework Program (FP7) Translational Cancer Research (TRANSCAN) Framework, the Foundation ARC pour la Recherche sur le Cancer (France), Plan Cancer-Eva-Inserm research grant, La direction 1énérale de l’offre de soins (DGOS), and INSERM (SIRIC LYriCAN, INCa-DGOS-Inserm_12563; to Z. Herceg). V. Miranda-Gonc¸alves was supported by NORTE-01-0145-740 FEDER-000027 (ESTIMA). M.I. Parker was jointly supported by the SAMRC with funds received from the National Department of Health and the Medical Research Council (MRC) UK with funds from the UK Government’s Newton Fund and GlaxoSmithKline (GSK). Kenyan case–control study was supported by the IARC and NIH/NCI (grant number R21CA191965). The Ethiopian case–control study was funded by the American Cancer Society (ACS) and IARC.
Publisher Copyright:
© 2021 American Association for Cancer Research.
ASJC Scopus subject areas
- Oncology
- Cancer Research
