Combined DNA methylation and gene expression profiling in gastrointestinal stromal tumors reveals hypomethylation of <i>SPP1</i> as an independent prognostic factor

Haller, Florian; Zhang, Jitao David; Moskalev, Evgeny A.; Braun, Alexander; Otto, Claudia; Geddert, Helene; Riazalhosseini, Yasser; Ward, Adrian; Balwierz, Aleksandra; Schaefer, Inga‐Marie; Cameron, Silke; Ghadimi, B. Michael; Agaimy, Abbas; Fletcher, Jonathan A.; Hoheisel, Jöerg; Hartmann, Arndt; Werner, Martin; Wiemann, Stefan; Şahin, Özgür

doi:10.1002/ijc.29088

Cited by 24 publications

(18 citation statements)

References 44 publications

(88 reference statements)

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“…62 For example, different DNA methylation profiles have been earlier reported in GISTs according to anatomic location of tumors. 35,63 Additionally, GIST-T1 cell line is dependent on the receptor tyrosine kinase KIT, whereas a secondary loss of KIT expression has been shown in the GIST48B line 64 suggesting the involvement of alternative mechanisms. Our study has several limitations.…”

Section: Discussionmentioning

confidence: 99%

Long noncoding RNA HOTAIR is upregulated in an aggressive subgroup of gastrointestinal stromal tumors (GIST) and mediates the establishment of gene‐specific DNA methylation patterns

Bure

Geer

Knopf

et al. 2018

Genes Chromosomes & Cancer

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Aberrant alterations of DNA methylation are common events in oncogenesis. The origin of cancer‐associated epigenetic defects is of interest for mechanistic understanding of malignant transformation and—in the long run—therapeutic modulation of DNA methylation in a locus‐specific manner. Given the ability of certain long noncoding RNAs to operate as an interface between DNA and the epigenetic modification machinery which can interact with DNA methyltransferases, we hypothesized—considering HOTAIR as an example—that this transcript may contribute to gene specificity of DNA methylation. Using gastrointestinal stromal tumors (GISTs, n = 67) as a model, we confirmed upregulation of HOTAIR in tumors with high risk of recurrence and showed high abundance of the transcript in GIST cell lines. HOTAIR knockdown in GIST‐T1 cells triggered transcriptional response of genes involved in the organization and disassembly of the extracellular matrix and, notably, induced global locus‐specific alterations of DNA methylation patterns. Hypomethylation was induced at a total of 507 CpG sites, whereas 382 CpG dinucleotides underwent gain of methylation upon HOTAIR depletion. Importantly, orchestrated gain or loss of methylation at multiple individual CpG sites was shown for cancer‐related DPP4, RASSF1, ALDH1A3, and other targets. Collectively, our data indicate that HOTAIR enables target specificity of DNA methylation in GIST and is capable of dual (hypo‐ and hypermethylation) regulation by a yet to be defined mechanism. The results further suggest the feasibility of manipulating DNA methylation in a targeted manner and are of interest in the context of epigenetic cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Long noncoding RNA HOTAIR is upregulated in an aggressive subgroup of gastrointestinal stromal tumors (GIST) and mediates the establishment of gene‐specific DNA methylation patterns

Bure

Geer

Knopf

et al. 2018

Genes Chromosomes & Cancer

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“…Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms that arise from the interstitial cells of Cajal (ICC), or their precursor stem cells [1]. GIST was initially a purely descriptive term coined in 1983 by Mazur and Clark to define intra-abdominal tumors that were definitely not carcinomas [2, 3].…”

Section: Introductionmentioning

confidence: 99%

Beyond standard therapy: drugs under investigation for the treatment of gastrointestinal stromal tumor

Alturkmani

Pessetto

Godwin

2015

Expert Opinion on Investigational Drugs

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Introduction Gastrointestinal stromal tumor (GIST) is the most common non-epithelial malignancy of the GI tract. With the discovery of KIT and later PDGFRA gain-of-function mutations as factors in the pathogenesis of the disease, GIST was the quintessential model for targeted therapy. Despite the successful clinical use of imatinib mesylate, a selective receptor tyrosine kinase (RTK) inhibitor that targets KIT, PDGFRA and BCR-ABL, we still do not have treatment for the long-term control of advanced GIST. Areas covered This review summarizes the drugs that are under investigation or have been assessed in trials for GIST treatment. The article focuses on their mechanisms of actions, the preclinical evidence of efficacy, and the clinical trials concerning safety and efficacy in humans. Expert opinion It is known that KIT and PDGFRA mutations in GIST patients influence the response to treatment. This observation should be taken into consideration when investigating new drugs. RECIST was developed to help uniformly report efficacy trials in oncology. Despite the usefulness of this system, many questions are being addressed about its validity in evaluating the true efficacy of drugs knowing that new targeted therapies do not affect the tumor size as much as they halt progression and prolong survival.

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“…Haller et al [59] also recorded SPP1 gene hypomethylation in GISTs [59]. SPP1 is significantly hypomethylated in a non-island CpG outside the promoter in patients with shorter survival, and it is considered a prognostic marker of GIST tumor malignancy in intermediary-risk groups [59].…”

Section: Dna Hypomethylation In Gistsmentioning

confidence: 99%

Epigenetics: an alternative pathway in GISTs tumorigenesis

Jašek¹,

Kasubova²,

Holubeková³

et al. 2018

neo

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Many diseases have different pathological backgrounds responsible for abnormal cell behavior and exhibiting altered function and signal transduction. This is especially true for tumors and although changes affecting DNA sequence, irreversible mutations and chromosomal aberrations in gastrointestinal stromal tumors (GISTs) have been widely studied, the importance of reversible epigenetic changes increasingly recognized in many cancers has received insufficient attention in these tumors. Epigenetic mechanisms are part of normal development and gene expression under normal conditions, but malfunction of these processes leads to malignant transformation by disturbing both intra- and intercellular communication. GISTs are a specific group of gastrointestinal tract tumors resistant to conventional chemotherapy and radiotherapy. Although they account for only 1% to 2% of tumors, they are among the most widespread gastrointestinal mesenchymal tumors. DNA hyper/hypomethylation overexpression/underexpression of miRNAs or abnormal histone modification may provide an alternative to the genetic modifications responsible for GIST pathology, response to treatment, prognosis and overall survival. This review summarizes the known epigenetic mechanisms involved in GIST pathogenesis; including onset, progression, and GISTs resistance. Reversible epigenetic changes are a novel and appropriate approach to halt the spread of metastases and the emergence of resistance in GIST treatment, and these changes depend on the type of epigenetic alternation, including inhibitors of histone acetyltranferase and deacetylase and DNA methyltransferases.

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Combined DNA methylation and gene expression profiling in gastrointestinal stromal tumors reveals hypomethylation of SPP1 as an independent prognostic factor

Cited by 24 publications

References 44 publications

Long noncoding RNA HOTAIR is upregulated in an aggressive subgroup of gastrointestinal stromal tumors (GIST) and mediates the establishment of gene‐specific DNA methylation patterns

Long noncoding RNA HOTAIR is upregulated in an aggressive subgroup of gastrointestinal stromal tumors (GIST) and mediates the establishment of gene‐specific DNA methylation patterns

Beyond standard therapy: drugs under investigation for the treatment of gastrointestinal stromal tumor

Epigenetics: an alternative pathway in GISTs tumorigenesis

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