Global DNA hypomethylation of colorectal tumours detected in tissue and liquid biopsies may be related to decreased methyl-donor content

Medientyp: E-Artikel
Titel: Global DNA hypomethylation of colorectal tumours detected in tissue and liquid biopsies may be related to decreased methyl-donor content
Beteiligte: Szigeti, Krisztina A.; Kalmár, Alexandra; Galamb, Orsolya; Valcz, Gábor; Barták, Barbara K.; Nagy, Zsófia B.; Zsigrai, Sára; Felletár, Ildikó; V. Patai, Árpád; Micsik, Tamás; Papp, Márton; Márkus, Eszter; Tulassay, Zsolt; Igaz, Peter; Takács, István; Molnár, Béla
Erschienen: Springer Science and Business Media LLC, 2022
Erschienen in: BMC Cancer
Sprache: Englisch
DOI: 10.1186/s12885-022-09659-1
ISSN: 1471-2407
Schlagwörter: Cancer Research ; Genetics ; Oncology
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Beschreibung: <jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Hypomethylation of long interspersed nuclear element 1 (LINE-1) is characteristic of various cancer types, including colorectal cancer (CRC). Malfunction of several factors or alteration of methyl-donor molecules’ (folic acid and S-adenosylmethionine) availability can contribute to DNA methylation changes. Detection of epigenetic alterations in liquid biopsies can assist in the early recognition of CRC. Following the investigations of a Hungarian colon tissue sample set, our goal was to examine the LINE-1 methylation of blood samples along the colorectal adenoma-carcinoma sequence and in inflammatory bowel disease. Moreover, we aimed to explore the possible underlying mechanisms of global DNA hypomethylation formation on a multi-level aspect.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>LINE-1 methylation of colon tissue (<jats:italic>n</jats:italic> = 183) and plasma (<jats:italic>n</jats:italic> = 48) samples of healthy controls and patients with colorectal tumours were examined with bisulfite pyrosequencing. To investigate mRNA expression, microarray analysis results were reanalysed in silico (<jats:italic>n</jats:italic> = 60)<jats:italic>.</jats:italic>Immunohistochemistry staining was used to validate DNA methyltransferases (<jats:italic>DNMTs)</jats:italic>and folate receptor beta<jats:italic>(FOLR2)</jats:italic>expression along with the determination of methyl-donor molecules’ in situ level (<jats:italic>n</jats:italic> = 40).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Significantly decreased LINE-1 methylation level was observed in line with cancer progression both in tissue (adenoma: 72.7 ± 4.8%, and CRC: 69.7 ± 7.6% vs. normal: 77.5 ± 1.7%,<jats:italic>p</jats:italic> ≤ 0.01) and liquid biopsies (adenoma: 80.0 ± 1.7%, and CRC: 79.8 ± 1.3% vs. normal: 82.0 ± 2.0%,<jats:italic>p</jats:italic> ≤ 0.01). However, no significant changes were recognized in inflammatory bowel disease cases. According to in silico analysis of microarray data, altered mRNA levels of several DNA methylation-related enzymes were detected in tumours vs. healthy biopsies, namely one-carbon metabolism-related genes—which met our analysing criteria—showed upregulation, while<jats:italic>FOLR2</jats:italic>was downregulated. Using immunohistochemistry,<jats:italic>DNMTs,</jats:italic>and<jats:italic>FOLR2</jats:italic>expression were confirmed. Moreover, significantly diminished folic acid and S-adenosylmethionine levels were observed in parallel with decreasing 5-methylcytosine staining in tumours compared to normal adjacent to tumour tissues (<jats:italic>p</jats:italic> ≤ 0.05).</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Our results suggest that LINE-1 hypomethylation may have a distinguishing value in precancerous stages compared to healthy samples in liquid biopsies. Furthermore, the reduction of global DNA methylation level could be linked to reduced methyl-donor availability with the contribution of decreased<jats:italic>FOLR2</jats:italic>expression.</jats:p></jats:sec>
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