Identification of DNA methylation markers for early detection of CRC indicates a role for nervous system-related genes in CRC

Glenn Rademakers, Maartje Massen, Alexander Koch, Muriel X. Draht, Nikkie Buekers, Kim A.D. Wouters, Nathalie Vaes, Tim De Meyer, Beatriz Carvalho, Gerrit A. Meijer, James G. Herman, Kim M. Smits, Manon van Engeland, Veerle Melotte*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

11 Citations (Scopus)

Abstract

Purpose: Colonoscopy and the fecal immunochemical test (FIT) are currently the most widely used screening modalities for colorectal cancer (CRC), however, both with their own limitations. Here we aim to identify and validate stool-based DNA methylation markers for the early detection of CRC and investigate the biological pathways prone to DNA methylation. Methods: DNA methylation marker discovery was performed using The Cancer Genome Atlas (TCGA) colon adenocarcinoma data set consisting of normal and primary colon adenocarcinoma tissue. The performance of the five best candidate markers and a previously identified marker, NDRG4, was evaluated on tissues and whole stool samples of healthy subjects and CRC patients using quantitative MSP assays. The results were compared and combined with FIT data. Finally, pathway and gene ontology enrichment analyses were performed using ToppFun, GOrilla and clusterProfiler. Results: GDNF, HAND2, SLC35F3, SNAP91 and SORCS1 were ranked as the best performing markers. Gene combinations of all five markers, NDRG4 and FIT were evaluated to establish the biomarker panel with the highest diagnostic potential, resulting in the identification of GDNF/SNAP91/NDRG4/FIT as the best performing marker panel. Pathway and gene ontology enrichment analyses revealed that genes associated with the nervous system were enriched in the set of best performing CRC-specific biomarkers. Conclusion: In silico discovery analysis using TCGA-derived data yielded a novel DNA-methylation-based assay for the early detection of CRC, potentially improving current screening modalities. Additionally, nervous system-related pathways were enriched in the identified genes, indicating an epigenetic regulation of neuronal genes in CRC.

Original languageEnglish
Article number80
JournalClinical Epigenetics
Volume13
Issue number1
DOIs
Publication statusPublished - 15 Apr 2021

Bibliographical note

Funding Information:
This work was supported financially by KWF Kankerbestrijding grant (UM-2-13-6075) and by SU2C-DCS International Translational Cancer Research Dream Team Grant (Stand Up To Cancer (SU2C)-AACR- DT1415, MEDOCC). SU2C is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research.

Funding Information:
This work was supported financially by KWF Kankerbestrijding grant (UM-2-13-6075) and by SU2C-DCS International Translational Cancer Research Dream Team Grant (Stand Up To Cancer (SU2C)-AACR- DT1415, MEDOCC). SU2C is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research.

Publisher Copyright:
© 2021, The Author(s).

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