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Gastrointestinal Stromal Tumor Enhancers Support a Transcription Factor Network Predictive of Clinical Outcome

ABSTRACT: Activating mutations in the KIT or PDGFRA receptor tyrosine kinases are hallmarks of gastrointestinal stromal tumor (GIST). The biological underpinnings of recurrence following resection or disease progression beyond kinase mutation are poorly understood. Utilizing chromatin immunoprecipitation with sequencing (ChIP-seq) of tumor samples and cell lines, we describe the enhancer landscape of GIST, highlighting genes that reinforce and extend our understanding of these neoplasms. A group of core transcription factors can be distinguished from others unique to localized and metastatic disease. The transcription factor HAND1 emerges in metastatic disease, binds to established GIST-associated enhancers and is required for GIST cell proliferation and KIT gene expression. The pattern of transcription factor expression in primary tumors is predictive of metastasis-free survival in GIST patients. These results provide insight into the enhancer landscape and transcription factor network underlying GIST, and define a new strategy for predicting clinical behavior of this disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE95862 | GEO | 2018/05/21

REPOSITORIES: GEO

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Gastrointestinal Stromal Tumor Enhancers Support a Transcription Factor Network Predictive of Clinical Outcome

Project description:Activating mutations in the KIT or PDGFRA receptor tyrosine kinases are hallmarks of gastrointestinal stromal tumor (GIST). The biological underpinnings of recurrence following resection or disease progression beyond kinase mutation are poorly understood. Utilizing chromatin immunoprecipitation with sequencing (ChIP-seq) of tumor samples and cell lines, we describe the enhancer landscape of GIST, highlighting genes that reinforce and extend our understanding of these neoplasms. A group of core transcription factors can be distinguished from others unique to localized and metastatic disease. The transcription factor HAND1 emerges in metastatic disease, binds to established GIST-associated enhancers and is required for GIST cell proliferation and KIT gene expression. The pattern of transcription factor expression in primary tumors is predictive of metastasis-free survival in GIST patients. These results provide insight into the enhancer landscape and transcription factor network underlying GIST, and define a new strategy for predicting clinical behavior of this disease.

2018-05-21 | GSE95861 | GEO

Gastrointestinal Stromal Tumor Enhancers Support a Transcription Factor Network Predictive of Clinical Outcome

2018-05-21 | GSE95863 | GEO

Anatomic and transcriptional determinants of gastrointestinal stromal tumor

Project description:Malignant transformation of the interstitial cells of Cajal (ICC) or their precursors gives rise to gastrointestinal stromal tumor (GIST). This mesenchymal neoplasm is characterized by activating mutations in the receptor tyrosine kinases KIT, or other less common mutational subtypes. GIST relies on a highly conserved core transcription factor (TF) network, with expression of accessory disease-state specific TFs. In this study, we define the divergent transcriptional programs supported by accessory TFs HAND1 and BARX1, with HAND1 modulating core TF and KIT gene expression to support GIST cell proliferation. HAND1 was expressed primarily in KIT mutant tumors, including the majority of metastatic tumors or those derived from small bowel, which intrinsically portend a more aggressive clinical course. Assessing archival GIST specimens, HAND1 and BARX1 expression patterns were superior predictors of relapse free survival compared to standard risk stratification. Metastatic tumors expressing HAND1 had a shorter progression free survival on first-line imatinib than those that were HAND1-negative. In contrast, BARX1 expression was enriched in more indolent forms of GIST. Signifying developmental origins of accessory TF expression, HAND1 was expressed solely in ICCs derived from the small intestine, while BARX1 expression was restricted to ICCs of the stomach. These results define the anatomic and transcriptional determinants of GIST clinical phenotypes, and may provide important biomarkers of disease risk stratification in GIST that will inform clinical decision making.

2022-05-23 | GSE151323 | GEO

Enhancer Domains in Gastrointestinal Stromal Tumor Regulate KIT Expression and are Targetable by BET Bromodomain Inhibition [ChIP-seq]

Project description:Gastrointestinal stromal tumor (GIST) is a mesenchymal neoplasm characterized by activating mutations in the related receptor tyrosine kinases KIT or PDGFRA. GIST relies on expression of these unamplified receptor tyrosine kinase (RTK) genes through a large enhancer domain, producing high expression levels of the oncogene required for tumor growth. Though kinase inhibition is an effective therapy for many GIST patients, disease progression from kinase resistance mutations is common, and no other efficacious classes of systemic therapy exist. Given GIST’s reliance upon enhancer-driven expression of an RTK, we hypothesized that the enhancer domain could be therapeutically targeted by a BET bromodomain inhibitor (BBI). Treatment of GIST cells with BBIs led to cell cycle arrest, apoptosis and cell death, with unique sensitivity in GIST cells arising from attenuation of the KIT enhancer domain and reduced KIT gene expression. BBI treatment in KIT-dependent GIST cells produced genome-wide changes in the H3K27ac enhancer landscape and gene expression program, which was also seen with direct KIT inhibition using a tyrosine kinase inhibitor (TKI). Combination treatment with BBI and TKI led to synergistic cytotoxic effects in vitro and in vivo, with BBIs preventing tumor growth in TKI-resistant xenografts. A novel mechanism of resistance to select BBIs was found in GIST attributable to drug efflux pumps. These results define a therapeutic vulnerability and clinical strategy for targeting oncogenic kinase dependency in GIST.

2019-01-23 | GSE113207 | GEO

Enhancer Domains in Gastrointestinal Stromal Tumor Regulate KIT Expression and are Targetable by BET Bromodomain Inhibition [RNA-seq]

2019-01-23 | GSE113215 | GEO

Kinome Profiling of Gastrointestinal Stromal Tumors Using Multiplexed Inhibitor Beads and Mass Spectrometry Identifies Wee1 as a Candidate Therapeutic Target

Project description:Purpose: Management of gastrointestinal stromal tumor (GIST) has been revolutionized by the identification of activating mutations in KIT and PDGFRA and the clinical application of receptor tyrosine kinase (RTK) inhibitors in the advanced disease setting. Stratification of GIST into molecularly defined subsets provides insight into clinical behavior and response to approved targeted therapies. Although these RTK inhibitors are effective in the majority of GIST, resistance to these agents remains a significant clinical obstacle. Development of effective treatment strategies for refractory GIST requires identification of novel targets to provide additional therapeutic options. Global kinome profiling has the potential to identify critical signaling networks and reveal protein kinases that are essential in GIST. Experimental Design: Using Multiplexed Inhibitor Beads and Mass Spectrometry paired with a super-SILAC kinome standard, we explored the majority of the kinome in GIST specimens from three GIST subtypes (KIT-mutant, PDGFRA-mutant and succinate dehydrogenase-deficient GIST) to identify novel kinase targets. In vitro and in vivo studies were performed to evaluate the utility of targeting the identified kinases in GIST. Results: Kinome profiling revealed distinct signatures in three GIST subtypes. PDGFRA-mutant GIST had elevated tumor associated macrophage (TAM) kinases and immunohistochemical analysis confirmed increased TAMs present in these tumors. Kinome profiling with loss-of-function assays revealed a significant role for G2-M tyrosine kinase, Wee1, in GIST survival. In vitro and in vivo studies revealed significant efficacy of MK-1775 (Wee1 inhibitor) in combination with avapritinib in both KIT and PDGFRA-mutant GIST cell lines, as well as notable efficacy of MK-1775 as a single agent in the PDGFRA-mutant line. Conclusions: These studies provide strong preclinical justification for the use of MK-1775 in GIST.

2021-09-09 | PXD020720 | Pride

Identification of common features proffered by KIT and PDGFRA mutations in gastro-intestinal stromal tumors

Project description:Mutations in KIT proto-oncogene receptor tyrosine kinase (KIT) or platelet derived growth factor receptor alpha (PDGFRA) are responsible for more than 85% of the gastrointestinal stromal tumors (GIST). The introduction of imatinib in the therapy scheme of GIST revolutionized the patient outcome. Unfortunately, the therapy allows a disease stabilization rather than curation. Resistance to the inhibitor arises in most cases within the two first years of therapy. The identification of new targets to treat GIST is now essential. We propose a thorough investigation of the activating mechanisms derived from the main PDGFRA and KIT mutants encountered in the GIST landscape. We identified striking differences among the different KIT mutants while PDGFRA mutants delivered a very uniform picture. KIT Exon 11 deletion mutant exhibited the highest intrinsic kinase activity and all KIT mutants were, in addition to their constitutive activation, responsive to stem cell factor (SCF) stimulation. This highlights the importance of evaluating the SCF expression profile in GIST patients. In contrast, PDGFRA mutants were not responsive to their ligand, PDGFAA, and displayed a very high intrinsic kinase activity. At the transcriptomic level, the mitogen-activated protein kinase (MAPK) pathway was established as the most prominent activated pathway, commonly up-regulated by all PDGFRA and KIT mutants. Inhibition of this pathway using the MEK inhibitor PD0325901 reduced the proliferation of GIST primary cells in the nanomolar range. This demonstrates the high value of MEK inhibitors for combination therapy in GIST treatment. This experiment contains expression data from HEK-293 cells expressing wild-type and mutant KIT. The mutants included in the study correspond to the main mutations found in GIST, mainly KIT Ex9 exhibits a duplication of AY502-503 and KIT Ex11 a deletion of residues 553 to 557.

2017-07-05 | E-MTAB-4548 | biostudies-arrayexpress

Mutant p63 affects epidermal cell identity through rewiring the enhancer landscape

Project description:<p>Transcription factor p63 is a key regulator of epidermal keratinocyte proliferation and differentiation. Mutations in the p63 DNA-binding domain are associated with Ectrodactyly Ectodermal Dysplasia Cleft Lip/Palate (EEC) syndrome. Underlying molecular mechanism of these mutations however remain unclear. Here we characterized the transcriptome and epigenome of p63 mutant keratinocytes derived from EEC patients. The transcriptome of p63 mutant keratinocytes deviated from the normal epidermal cell identity. Epigenomic analyses showed an altered enhancer landscape in p63 mutant keratinocytes contributed by loss of p63-bound active enhancers and by unexpected gain of enhancers. The gained enhancers were frequently bound by deregulated transcription factors such as RUNX1. Reversing RUNX1 overexpression partially rescued deregulated gene expression and the altered enhancer landscape. Our findings identify an unreported disease mechanism whereby mutant p63 rewires the enhancer landscape and affects epidermal cell identity, consolidating the pivotal role of p63 in controlling the enhancer landscape of epidermal keratinocytes.</p>

| phs001737 | dbGaP

Genes differentially expressed in primary and metastatic liver GISTs.

Project description:Although the main cause of gastrointestinal stromal tumor (GIST) is due to gain-of-function mutation of the c-kit gene in the interstitial cells of Cajal, concomitant genetic or epigenetic changes other than c-kit are thought to occur in the development of metastasis. We used microarrays to identify genes that were up-regulated and down-regulated in the metastatic liver GIST.

2010-04-13 | GSE21315 | GEO

Project description:GIST-KIT-PDGFRA

| PRJNA824718 | ENA