Dataset Information

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

ABSTRACT: Introduction:The majority of desmoid-type fibromatosis (DTF) tumors harbor a ?-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 ?-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 ?-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.

SUBMITTER: Timbergen MJM

PROVIDER: S-EPMC7658920 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Timbergen Milea J M MJM Boers Ruben R Vriends Anne L M ALM Boers Joachim J van IJcken Wilfred F J WFJ Lavrijsen Marla M Grünhagen Dirk J DJ Verhoef Cornelis C Sleijfer Stefan S Smits Ron R Gribnau Joost J Wiemer Erik A C EAC

Frontiers in oncology 20201029

<h4>Introduction</h4>The majority of desmoid-type fibromatosis (DTF) tumors harbor a β-catenin mutation, affecting specific codons in <i>CTNNB1</i> 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 t ...[more]

PMID: 33194643

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Project description:Desmoid fibromatosis is a rare but locally aggressive tumor comprised of myofibroblasts. Desmoids do not have the ability to metastasize but can cause significant morbidity and mortality by local invasion. These tumors may occur throughout the body, but are commonly found on the abdominal wall and within the intestinal mesentery. Desmoids in these areas may cause unique clinical problems for physicians and patients. Mutations in either the β-catenin or the APC genes are usually the cause for the development of these tumors with the former comprising the sporadic development of tumors and the latter being associated with familial adenomatous polyposis syndrome. Surgical resection with histologically negative margins has been the cornerstone of therapy for this disease, but this paradigm has begun to shift. It is now common to accept a microscopically positive margin after resection as recurrence rates may not be significantly affected. An even more radical evolution in management has been the recent movement towards "watchful waiting" when new desmoids are diagnosed. As the natural history of desmoids has become better understood, it is evident that some tumors will not grow and may even spontaneously regress sparing patients the morbidity of more aggressive therapy. Other modalities of treatment for desmoids include radiation and systemic therapy which both can be used adjuvantly or as definitive therapy and have shown durable response rates as single therapy regimens. The decision to use radiation and/or systemic therapies is often based on tumor biology, tumor location, surgical morbidity, and patient preference. Systemic therapy options have increased to include hormonal therapies, non-steroidal anti-inflammatory drugs and chemotherapy, as well as targeted therapies. Unfortunately, the rarity of this disease has resulted in a scarcity of randomized trials to evaluate any of these therapies emphasizing the need for this disease to be treated at high volume multidisciplinary institutions.

Dataset Information

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

Publications

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

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