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DNA methylation changes in genes frequently mutated in sporadic colorectal cancer and in the DNA repair and Wnt/beta-catenin signaling pathway genes
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Laboratory Medicine.
Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic; nstitute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Prague, Czech Republic.
Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic; nstitute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Prague, Czech Republic; Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Czech Republic.
Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic; nstitute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Prague, Czech Republic.
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2014 (English)In: Epigenomics, ISSN 1750-1911, Vol. 6, no 2, 179-191 p.Article in journal (Refereed) Published
Abstract [en]

Aim: The onset and progression of colorectal cancer (CRC) involves a cascade of genetic and/or epigenetic events. The aim of the present study was to address the DNA methylation status of genes relevant in colorectal carcinogenesis and its progression, such as genes frequently mutated in CRC, genes involved in the DNA repair and Wnt signaling pathway.

Material & methods: We analyzed methylation status in totally 160 genes in 12 paired colorectal tumors and adjacent healthy mucosal tissues using the Illumina Infinium Human Methylation 450 BeadChip.

Results: We found significantly aberrant methylation in 23 genes (NEIL1, NEIL3, DCLRE1C, NHEJ1, GTF2H5, CCNH, CTNNB1, DKK2, DKK3, FZD5 LRP5, TLE3, WNT2, WNT3A, WNT6, TCF7L1, CASP8, EDNRB1, GPC6, KIAA1804, MYO1B, SMAD2 and TTN). External validation by mRNA expression showed a good agreement between hypermethylation in cancer and down-regulated mRNA expression of the genes EDNRB1, GPC6 and SMAD2, and between hypomethylation and up-regulated mRNA expression of the CASP8 and DCLRE1C genes.

Conclusion: Aberrant methylation of the DCLRE1C and GPC6 genes are presented here for the first time and are therefore of special interest for further validation as novel candidate biomarker genes in CRC, and merit further validation with specific assays.

Place, publisher, year, edition, pages
Future Medicine , 2014. Vol. 6, no 2, 179-191 p.
Keyword [en]
CpG, DNA repair genes, Infinium Human Methylation 450 BeadChip, methylation status, sporadic colorectal cancer, Wnt/beta-catenin signaling pathway
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Medical Genetics
Research subject
Biomedicine
Identifiers
URN: urn:nbn:se:oru:diva-35867DOI: 10.2217/EPI.14.7ISI: 000335684900015PubMedID: 24811787Scopus ID: 2-s2.0-84900412412OAI: oai:DiVA.org:oru-35867DiVA: diva2:736554
Note

Funding agencies:

CZ:GA CR GA Grant numbers: P304/11/P715 P304/12/1585

IGA:NT Grant number: 14329

Lions Cancer Foundation

Nyckelfonden

Örebro läns landsting 

Available from: 2014-08-07 Created: 2014-08-07 Last updated: 2017-10-18Bibliographically approved
In thesis
1. DNA methylation in the placenta and in cancerwith special reference to folate transporting genes
Open this publication in new window or tab >>DNA methylation in the placenta and in cancerwith special reference to folate transporting genes
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

DNA methylation is an epigenetic mechanism that regulates the gene transcription. Folate is used in cellular synthesis of methyl groups, nucleic acids and amino acids. In complex diseases like cancer and neural tube defects (NTD), various genetic and epigenetic alterations can be found that disrupt the normal cell function. The main goals of this thesis were to analyze whether the genes responsible for the folate transport (FOLR1, PCFT, and RFC1) could be regulated by DNA methylation in placenta, blood leukocytes and colorectal cancer. We also addressed the genome-wide DNA methylation changes in colorectal cancer andcervical cancer.We found that changes in the methylated fraction of the RFC1 gene were dependent on the RFC1 80G>A polymorphism in placental specimens with NTDs and blood leukocytes from subjects with high homocysteine (Paper I). In colorectal cancer, the greatest difference in DNA methylation was observed in the RFC1 gene and was related to a lower protein expression (Paper II).In Paper III and IV we studied the DNA methylated fraction using a high-density array. Paper III was focused on genes in the DNA repair pathway and frequently mutated in colorectal cancer. We found that aberrant methylation in the DNA mismatch repair genes was not a frequent event in colorectal cancer and we identified five candidate biomarker genes in colorectal cancer, among them the GPC6 and DCLRE1C genes. In Paper IV, we found hypomethylation of genes involved in the immune system in cervical cancer specimens compared to healthy cervical scrapes and we identified twenty four candidate genes for further evaluation ofclinical value.In conclusion, the work of this thesis filled a relevant knowledge gap regarding the role of differential methylation of the folate transport genes in NTD and colorectal cancer. This thesis work also provided insights into the functional role of DNA methylation in cancer specific pathways and identified potential novel biomarker genes.

Place, publisher, year, edition, pages
Örebro: Örebro university, 2014. 67 p.
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 100
Keyword
DNA methylation, CRC, placenta, cervix, leukocytes, T-DMRs, folate, array, expression
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-32599 (URN)978-91-7668-986-8 (ISBN)
Public defence
2014-01-31, Wilandersalen, Universitetssjukhuset, S. Grev Rosengatan, 703 62 Örebro, 09:15 (English)
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Available from: 2013-12-02 Created: 2013-12-02 Last updated: 2017-10-17Bibliographically approved

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Farkas, Sanja A.Nilsson, Torbjörn K.
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