Hypermethylation of PDX1, EN2, and MSX1 predicts the prognosis of colorectal cancer.

Biomarkers, Tumor / genetics Colorectal Neoplasms / diagnosis CpG Islands / genetics DNA Methylation Homeodomain Proteins Humans MSX1 Transcription Factor / genetics Nerve Tissue Proteins Oncogenes Trans-Activators

Journal

Experimental & molecular medicine
ISSN: 2092-6413
Titre abrégé: Exp Mol Med
Pays: United States
ID NLM: 9607880

Informations de publication

Date de publication:
02 2022
Historique:
received: 13 07 2021
accepted: 18 11 2021
revised: 12 11 2021
pubmed: 17 2 2022
medline: 20 4 2022
entrez: 16 2 2022
Statut: ppublish

Résumé

Despite numerous observations regarding the relationship between DNA methylation changes and cancer progression, only a few genes have been verified as diagnostic biomarkers of colorectal cancer (CRC). To more practically detect methylation changes, we performed targeted bisulfite sequencing. Through co-analysis of RNA-seq, we identified cohort-specific DNA methylation markers: CpG islands of the intragenic regions of PDX1, EN2, and MSX1. We validated that these genes have oncogenic features in CRC and that their expression levels are increased in correlation with the hypermethylation of intragenic regions. The reliable depth of the targeted bisulfite sequencing data enabled us to design highly optimized quantitative methylation-specific PCR primer sets that can successfully detect subtle changes in the methylation levels of candidate regions. Furthermore, these methylation levels can divide CRC patients into two groups denoting good and poor prognoses. In this study, we present a streamlined workflow for screening clinically significant differentially methylated regions. Our discovery of methylation markers in the PDX1, EN2, and MSX1 genes suggests their promising performance as prognostic markers and their clinical application in CRC patients.

Identifiants

DOI: 10.1038/s12276-022-00731-1 PMID: 35169223 PMC: PMC8894425
pubmed: 35169223
doi: 10.1038/s12276-022-00731-1
pii: 10.1038/s12276-022-00731-1
pmc: PMC8894425
doi:

Substances chimiques

Biomarkers, Tumor 0
Homeodomain Proteins 0
MSX1 Transcription Factor 0
MSX1 protein, human 0
Nerve Tissue Proteins 0
Trans-Activators 0
engrailed 2 protein 0
pancreatic and duodenal homeobox 1 protein 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

156-168

Informations de copyright

© 2022. The Author(s).

Références

Ferlay, J. et al. Global Cancer Observatory: Cancer Today. IARC https://gco.iarc.fr/today (2020).
Day, D. W. The adenoma-carcinoma sequence. Scand. J. Gastroenterol. Suppl. 104, 99–107 (1984).
pubmed: 6597553
Dekker, E., Tanis, P. J., Vleugels, J. L. A., Kasi, P. M. & Wallace, M. B. Colorectal cancer. Lancet 394, 1467–1480 (2019).
pubmed: 31631858 doi: 10.1016/S0140-6736(19)32319-0
Vogelstein, B. & Kinzler, K. W. Cancer genes and the pathways they control. Nat. Med. 10, 789–799 (2004).
pubmed: 15286780 doi: 10.1038/nm1087
Zecchin, D. et al. BRAF V600E is a determinant of sensitivity to proteasome inhibitors. Mol. Cancer Ther. 12, 2950–2961 (2013).
pubmed: 24107445 doi: 10.1158/1535-7163.MCT-13-0243
Schell, M. J. et al. A multigene mutation classification of 468 colorectal cancers reveals a prognostic role for APC. Nat. Commun. 7, 11743 (2016).
pubmed: 27302369 pmcid: 4912618 doi: 10.1038/ncomms11743
Xia, L. C. et al. Whole genome analysis identifies the association of TP53 genomic deletions with lower survival in Stage III colorectal cancer. Sci. Rep. 10, 5009 (2020).
pubmed: 32193467 pmcid: 7081316 doi: 10.1038/s41598-020-61643-6
SEER Cancer Stat Facts: Colorectal Cancer. National Cancer Institute https://seer.cancer.gov/statfacts/html/colorect.html (2020).
Dashwood, R. H. Early detection and prevention of colorectal cancer (review). Oncol. Rep. 6, 277–281 (1999).
pubmed: 10022989
Force, U. S. P. S. T. et al. Screening for colorectal cancer: US preventive services task force recommendation statement. JAMA 315, 2564–2575 (2016).
doi: 10.1001/jama.2016.5989
Feinberg, A. P. & Vogelstein, B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301, 89–92 (1983).
pubmed: 6185846 doi: 10.1038/301089a0
Ehrlich, M. DNA methylation in cancer: too much, but also too little. Oncogene 21, 5400–5413 (2002).
pubmed: 12154403 doi: 10.1038/sj.onc.1205651
Rodriguez, J. et al. Chromosomal instability correlates with genome-wide DNA demethylation in human primary colorectal cancers. Cancer Res. 66, 8462–9468 (2006).
pubmed: 16951157 doi: 10.1158/0008-5472.CAN-06-0293
Toyota, M. et al. CpG island methylator phenotype in colorectal cancer. Proc. Natl Acad. Sci. USA 96, 8681–8686 (1999).
pubmed: 10411935 pmcid: 17576 doi: 10.1073/pnas.96.15.8681
Tóth, K. et al. Detection of methylated SEPT9 in plasma is a reliable screening method for both left- and right-sided colon cancers. PLoS ONE 7, e46000 (2012).
pubmed: 23049919 pmcid: 3457959 doi: 10.1371/journal.pone.0046000
A stool DNA test (Cologuard) for colorectal cancer screening. Med. Lett. Drugs Ther. 56, 100–101 (2014).
Peterse, E. F. P. et al. Comparing the cost-effectiveness of innovative colorectal cancer screening tests. J. Natl Cancer I. 113, 154–161 (2021).
doi: 10.1093/jnci/djaa103
Koch, A. et al. Analysis of DNA methylation in cancer: location revisited. Nat. Rev. Clin. Oncol. 15, 459–466 (2018).
pubmed: 29666440 doi: 10.1038/s41571-018-0004-4
Tse, J. W. T., Jenkins, L. J., Chionh, F. & Mariadason, J. M. Aberrant DNA methylation in colorectal cancer: what should we target? Trends Cancer 3, 698–712 (2017).
pubmed: 28958388 doi: 10.1016/j.trecan.2017.08.003
Jain, S. et al. Impact of the location of CpG methylation within the GSTP1 gene on its specificity as a DNA marker for hepatocellular carcinoma. PLoS ONE 7, e35789 (2012).
pubmed: 22536438 pmcid: 3335004 doi: 10.1371/journal.pone.0035789
Dedeurwaerder, S. et al. Evaluation of the Infinium Methylation 450 K technology. Epigenomics 3, 771–784 (2011).
pubmed: 22126295 doi: 10.2217/epi.11.105
Wendt, J., Rosenbaum, H., Richmond, T. A., Jeddeloh, J. A. & Burgess, D. L. Targeted bisulfite sequencing using the SeqCap Epi enrichment system. Methods Mol. Biol. 1708, 383–405 (2018).
pubmed: 29224155 doi: 10.1007/978-1-4939-7481-8_20
Herman, J. G., Graff, J. R., Myöhänen, S., Nelkin, B. D. & Baylin, S. B. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. P. Natl Acad. Sci. USA 93, 9821–9826 (1996).
doi: 10.1073/pnas.93.18.9821
Hernandez, H. G., Tse, M. Y., Pang, S. C., Arboleda, H. & Forero, D. A. Optimizing methodologies for PCR-based DNA methylation analysis. Biotechniques 55, 181–197 (2013).
pubmed: 24107250 doi: 10.2144/000114087
Kibbe, W. A. OligoCalc: an online oligonucleotide properties calculator. Nucleic Acids Res. 35, W43–W46 (2007).
pubmed: 17452344 pmcid: 1933198 doi: 10.1093/nar/gkm234
Klutstein, M., Nejman, D., Greenfield, R. & Cedar, H. DNA methylation in cancer and aging. Cancer Res. 76, 3446–3450 (2016).
pubmed: 27256564 doi: 10.1158/0008-5472.CAN-15-3278
Lu, J., Wilfred, P., Korbie, D. & Trau, M. Regulation of canonical oncogenic signaling pathways in cancer via DNA methylation. Cancers (Basel) 12, 3199 (2020).
doi: 10.3390/cancers12113199
Ng, J. M. & Yu, J. Promoter hypermethylation of tumour suppressor genes as potential biomarkers in colorectal cancer. Int. J. Mol. Sci. 16, 2472–2496 (2015).
pubmed: 25622259 pmcid: 4346847 doi: 10.3390/ijms16022472
Suzuki, M. M. & Bird, A. DNA methylation landscapes: provocative insights from epigenomics. Nat. Rev. Genet. 9, 465–476 (2008).
pubmed: 18463664 doi: 10.1038/nrg2341
Maunakea, A. K. et al. Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature 466, 253–257 (2010).
pubmed: 20613842 pmcid: 3998662 doi: 10.1038/nature09165
Lee, S. M. et al. Intragenic CpG islands play important roles in bivalent chromatin assembly of developmental genes. Proc. Natl Acad. Sci. USA 114, E1885–e1894 (2017).
pubmed: 28223506 pmcid: 5347632
Krinner, S. et al. CpG domains downstream of TSSs promote high levels of gene expression. Nucleic Acids Res. 42, 3551–3564 (2014).
pubmed: 24413563 pmcid: 3973331 doi: 10.1093/nar/gkt1358
Shenker, N. & Flanagan, J. M. Intragenic DNA methylation: implications of this epigenetic mechanism for cancer research. Br. J. Cancer 106, 248–253 (2012).
pubmed: 22166804 doi: 10.1038/bjc.2011.550
Kinde, B., Wu, D. Y., Greenberg, M. E. & Gabel, H. W. DNA methylation in the gene body influences MeCP2-mediated gene repression. Proc. Natl Acad. Sci. USA 113, 15114–15119 (2016).
pubmed: 27965390 pmcid: 5206576 doi: 10.1073/pnas.1618737114
Arechederra, M. et al. Hypermethylation of gene body CpG islands predicts high dosage of functional oncogenes in liver cancer. Nat. Commun. 9, 3164 (2018).
pubmed: 30089774 pmcid: 6082886 doi: 10.1038/s41467-018-05550-5
Greenberg, M. V. C. & Bourc’his, D. The diverse roles of DNA methylation in mammalian development and disease. Nat. Rev. Mol. Cell Bio. 20, 590–607 (2019).
doi: 10.1038/s41580-019-0159-6
Chandrashekar, D. S. et al. UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia 19, 649–658 (2017).
pubmed: 28732212 pmcid: 5516091
Teo, A. K. et al. PDX1 binds and represses hepatic genes to ensure robust pancreatic commitment in differentiating human embryonic stem cells. Stem Cell Rep. 4, 578–590 (2015).
doi: 10.1016/j.stemcr.2015.02.015
Lin, C.-P. & He, L. Noncoding RNAs in cancer development. Annu. Rev. Cancer Biol. 1, 163–184 (2017).
doi: 10.1146/annurev-cancerbio-050216-034443
Boons, G. et al. PDX1 DNA methylation distinguishes two subtypes of pancreatic neuroendocrine neoplasms with a different prognosis. Cancers (Basel) 12, 1461 (2020).
doi: 10.3390/cancers12061461
Vinogradova, T. V. & Sverdlov, E. D. PDX1: a unique pancreatic master regulator constantly changes its functions during embryonic development and progression of pancreatic cancer. Biochem. (Mosc.) 82, 887–893 (2017).
doi: 10.1134/S000629791708003X
Brunet, I. et al. The transcription factor Engrailed-2 guides retinal axons. Nature 438, 94–98 (2005).
pubmed: 16267555 pmcid: 3785142 doi: 10.1038/nature04110
Li, Y. et al. EN2 as an oncogene promotes tumor progression via regulating CCL20 in colorectal cancer. Cell Death Dis. 11, 604 (2020).
pubmed: 32732864 pmcid: 7393501 doi: 10.1038/s41419-020-02804-3
Sun, A. J. et al. Identification of MSX1 and DCLK1 as mRNA biomarkers for colorectal cancer detection through DNA methylation information. J. Cell Physiol. 232, 1879–1884 (2017).
pubmed: 27966796 doi: 10.1002/jcp.25733
Morita, S. et al. Targeted DNA demethylation in vivo using dCas9-peptide repeat and scFv-TET1 catalytic domain fusions. Nat. Biotechnol. 34, 1060–1065 (2016).
pubmed: 27571369 doi: 10.1038/nbt.3658
Su, J. et al. Homeobox oncogene activation by pan-cancer DNA hypermethylation. Genome Biol. 19, 108 (2018).
pubmed: 30097071 pmcid: 6085761 doi: 10.1186/s13059-018-1492-3
Imperiale, T. F. et al. Multitarget stool DNA testing for colorectal-cancer screening. N. Engl. J. Med. 370, 1287–1297 (2014).
pubmed: 24645800 doi: 10.1056/NEJMoa1311194
Lu, H. et al. DNA methylation analysis of SFRP2, GATA4/5, NDRG4 and VIM for the detection of colorectal cancer in fecal DNA. Oncol. Lett. 8, 1751–1756 (2014).
pubmed: 25202404 pmcid: 4156205 doi: 10.3892/ol.2014.2413
Liu, Y. et al. Serum methylation levels of TAC1. SEPT9 and EYA4 as diagnostic markers for early colorectal cancers: a pilot study. Biomarkers 18, 399–405 (2013).
pubmed: 23862763 doi: 10.3109/1354750X.2013.798745
Pedersen, S. K. et al. Evaluation of an assay for methylated BCAT1 and IKZF1 in plasma for detection of colorectal neoplasia. BMC Cancer 15, 654 (2015).
pubmed: 26445409 pmcid: 4596413 doi: 10.1186/s12885-015-1674-2

Auteurs

Yeongun Lee (Y)

Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea.

So Hee Dho (SH)

Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea.

Jiyeon Lee (J)

Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea.

Ji-Hyun Hwang (JH)

Interdisciplinary Program of Integrated OMICS for Biomedical Science, The Graduate School, Yonsei University, Seoul, South Korea.

Minjung Kim (M)

Interdisciplinary Program of Integrated OMICS for Biomedical Science, The Graduate School, Yonsei University, Seoul, South Korea.

Won-Young Choi (WY)

Interdisciplinary Program of Integrated OMICS for Biomedical Science, The Graduate School, Yonsei University, Seoul, South Korea.

Jin-Young Lee (JY)

Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.

Jongwon Lee (J)

Department of Biomedical Sciences, Korea University College of Medicine, Seoul, South Korea.

Woochul Chang (W)

Department of Biology Education, College of Education, Pusan National University, Busan, South Korea.
ORCID: 0000-0001-7367-2586

Min Young Lee (MY)

College of Pharmacy, Research Institute of Pharmaceutical Sciences, Vessel-Organ Interaction Research Center (MRC), Kyungpook National University, Daegu, South Korea.

Jungmin Choi (J)

Department of Biomedical Sciences, Korea University College of Medicine, Seoul, South Korea.
ORCID: 0000-0002-8614-0973

Tae-You Kim (TY)

Department of Internal Medicine, Seoul National University Hospital, Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Cancer Research Institute, Seoul National University, Seoul, South Korea. kimty@snu.ac.kr.

Lark Kyun Kim (LK)

Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea. lkkim@yuhs.ac.
ORCID: 0000-0001-5983-4470

Articles similaires

[Redispensing of expensive oral anticancer medicines: a practical application].

Lisanne N van Merendonk, Kübra Akgöl, Bastiaan Nuijen
1.00
Humans Antineoplastic Agents Administration, Oral Drug Costs Counterfeit Drugs

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female

Evaluation of Low-Value Services Across Major Medicare Advantage Insurers and Traditional Medicare.

Ciara Duggan, Adam L Beckman, Ishani Ganguli et al.
1.00
Humans United States Aged Cross-Sectional Studies Medicare Part C

Effectiveness of Virtual Yoga for Chronic Low Back Pain: A Randomized Clinical Trial.

Hallie Tankha, Devyn Gaskins, Amanda Shallcross et al.
1.00
Humans Yoga Low Back Pain Female Male

Classifications MeSH

questionsmedicales.fr › Facteurs biologiques › Marqueurs biologiques › Marqueurs biologiques tumoraux › Hypermethylation of PDX1, EN2, and MSX1...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladies gastro-intestinales › Maladies intestinales › Maladies du rectum › Tumeurs colorectales › Hypermethylation of PDX1, EN2, and MSX1...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Ilots CpG › Hypermethylation of PDX1, EN2, and MSX1...
questionsmedicales.fr › Phénomènes génétiques › Méthylation de l'ADN › Hypermethylation of PDX1, EN2, and MSX1...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de liaison à l'ADN › Protéines à homéodomaine › Hypermethylation of PDX1, EN2, and MSX1...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Hypermethylation of PDX1, EN2, and MSX1...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteur de transcription MSX-1 › Hypermethylation of PDX1, EN2, and MSX1...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de tissu nerveux › Hypermethylation of PDX1, EN2, and MSX1...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Gènes tumoraux › Oncogènes › Hypermethylation of PDX1, EN2, and MSX1...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines virales › Protéines virales régulatrices ou accessoires › Transactivateurs › Hypermethylation of PDX1, EN2, and MSX1...