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BMC Cancer
Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Research article

Gene promoter and exon DNA methylation changes in colon cancer development – mRNA expression and tumor mutation alterations

Authors: Béla Molnár, Orsolya Galamb, Bálint Péterfia, Barnabás Wichmann, István Csabai, András Bodor, Alexandra Kalmár, Krisztina Andrea Szigeti, Barbara Kinga Barták, Zsófia Brigitta Nagy, Gábor Valcz, Árpád V. Patai, Péter Igaz, Zsolt Tulassay

Published in: BMC Cancer | Issue 1/2018

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Abstract

Background

DNA mutations occur randomly and sporadically in growth-related genes, mostly on cytosines. Demethylation of cytosines may lead to genetic instability through spontaneous deamination. Aims were whole genome methylation and targeted mutation analysis of colorectal cancer (CRC)-related genes and mRNA expression analysis of TP53 pathway genes.

Methods

Long interspersed nuclear element-1 (LINE-1) BS-PCR followed by pyrosequencing was performed for the estimation of global DNA metlyation levels along the colorectal normal-adenoma-carcinoma sequence. Methyl capture sequencing was done on 6 normal adjacent (NAT), 15 adenomatous (AD) and 9 CRC tissues. Overall quantitative methylation analysis, selection of top hyper/hypomethylated genes, methylation analysis on mutation regions and TP53 pathway gene promoters were performed. Mutations of 12 CRC-related genes (APC, BRAF, CTNNB1, EGFR, FBXW7, KRAS, NRAS, MSH6, PIK3CA, SMAD2, SMAD4, TP53) were evaluated. mRNA expression of TP53 pathway genes was also analyzed.

Results

According to the LINE-1 methylation results, overall hypomethylation was observed along the normal-adenoma-carcinoma sequence. Within top50 differential methylated regions (DMRs), in AD-N comparison TP73, NGFR, PDGFRA genes were hypermethylated, FMN1, SLC16A7 genes were hypomethylated. In CRC-N comparison DKK2, SDC2, SOX1 genes showed hypermethylation, while ERBB4, CREB5, CNTN1 genes were hypomethylated. In certain mutation hot spot regions significant DNA methylation alterations were detected. The TP53 gene body was addressed by hypermethylation in adenomas. APC, TP53 and KRAS mutations were found in 30, 15, 21% of adenomas, and in 29, 53, 29% of CRCs, respectively. mRNA expression changes were observed in several TP53 pathway genes showing promoter methylation alterations.

Conclusions

DNA methylation with consecutive phenotypic effect can be observed in a high number of promoter and gene body regions through CRC development.
Appendix
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Metadata
Title
Gene promoter and exon DNA methylation changes in colon cancer development – mRNA expression and tumor mutation alterations
Authors
Béla Molnár
Orsolya Galamb
Bálint Péterfia
Barnabás Wichmann
István Csabai
András Bodor
Alexandra Kalmár
Krisztina Andrea Szigeti
Barbara Kinga Barták
Zsófia Brigitta Nagy
Gábor Valcz
Árpád V. Patai
Péter Igaz
Zsolt Tulassay
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-4609-x

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