Differentially Methylated Regions in Desmoid-Type Fibromatosis: A Comparison Between CTNNB1 S45F and T41A Tumors.

Autor:	Timbergen MJM; Department of Surgical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, Netherlands.; Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, Netherlands., Boers R; Department of Developmental Biology, Oncode Institute, Erasmus MC, University Medical Center, Rotterdam, Netherlands., Vriends ALM; Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, Netherlands., Boers J; Department of Developmental Biology, Oncode Institute, Erasmus MC, University Medical Center, Rotterdam, Netherlands., van IJcken WFJ; Center for Biomics, Erasmus MC, University Medical Center, Rotterdam, Netherlands., Lavrijsen M; Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, Netherlands., Grünhagen DJ; Department of Surgical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, Netherlands., Verhoef C; Department of Surgical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, Netherlands., Sleijfer S; Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, Netherlands., Smits R; Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, Netherlands., Gribnau J; Department of Developmental Biology, Oncode Institute, Erasmus MC, University Medical Center, Rotterdam, Netherlands., Wiemer EAC; Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, Netherlands.
Jazyk:	angličtina
Zdroj:	Frontiers in oncology [Front Oncol] 2020 Oct 29; Vol. 10, pp. 565031. Date of Electronic Publication: 2020 Oct 29 (Print Publication: 2020).
DOI:	10.3389/fonc.2020.565031
Abstrakt:	Introduction: The majority of desmoid-type fibromatosis (DTF) tumors harbor a β-catenin mutation, affecting specific codons in CTNNB1 exon 3. S45F tumors are reported to have a higher chance of recurrence after surgery and more resistance to systemic treatments compared to wild-type (WT) and T41A tumors. The aim of this pilot study was to examine the genome-wide DNA methylation profiles of S45F and T41A mutated DTF, to explain the observed differences in clinical behavior between these DTF subtypes. Material and Methods: Genome-wide analysis of DNA methylation was performed using MeD-seq on formalin-fixed, paraffin-embedded primary DTF samples harboring a S45F (n = 14) or a T41A (n = 15) mutation. Differentially methylated regions (DMRs) between S45F and T41A DTF were identified and used for a supervised hierarchical cluster analysis. DMRs with a fold-change ≥1.5 were considered to be differentially methylated and differences between S45F and T41A tumors were quantitatively assessed. The effect of DMRs on the expression of associated genes was assessed using an independent mRNA expression dataset. Protein-protein interactions between WT β-catenin and mutant variants and DNA methyltransferase 1 (DNMT1) were examined by immunoprecipitation experiments. Results: MeD-seq analyses indicated 354 regions that displayed differential methylation. Cluster analysis yielded no distinct clusters based on mutation, sex, tumor site or tumor size. A supervised clustering based on DMRs between small (≤34 mm) and large (>87 mm) DTF distinguished the two groups. Only ten DMRs displayed a fold change of ≥1.5 and six of them were found associated with the following genes: NLRP4 , FOXK2 , PERM1 , CCDC6 , NOC4L , and DUX4L6 . The effects of DMRs on gene expression yielded a significant difference (p < 0.05) in the expression between S45F and T41A for CCDC6 and FOXK2 but not for all Affymetrix probe-sets used to detect these genes. Immunoprecipitations did not reveal an association of WT β-catenin or mutant variants with DNMT1. Conclusion: This study demonstrated that S45F and T41A DTF tumors did not exhibit gross differences in DNA methylation patterns. This implies that distinct DNA methylation profiles are not the sole determinant for the divergent clinical behavior of these different DTF mutant subtypes. (Copyright © 2020 Timbergen, Boers, Vriends, Boers, van IJcken, Lavrijsen, Grünhagen, Verhoef, Sleijfer, Smits, Gribnau and Wiemer.)
Databáze:	MEDLINE
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