Pathogenesis Of Gastrointestinal Stromal Tumors Research Articles

Genomic and transcriptomic landscape of human gastrointestinal stromal tumors

Gastrointestinal stromal tumor (GISTs) are clinically heterogenous exhibiting varying degrees of disease aggressiveness in individual patients. We comprehensively describe the genomic and transcriptomic landscape of a cohort of 117 GISTs including 31 low-risk, 18 intermediate-risk, 29 high-risk, 34 metastatic and 5 neoadjuvant GISTs from 105 patients. GISTs have notably low tumor mutation burden but widespread copy number variations. Aggressive GISTs harbor remarkably more genomic aberrations than low-/intermediate-risk GISTs. Complex genomic alterations, chromothripsis and kataegis, occur selectively in aggressive GISTs. Despite the paucity of mutations, recurrent inactivating YLPM1 mutations are identified (10.3%, 7 of 68 patients), enriched in high-risk/metastatic GIST and functional study further demonstrates YLPM1 inactivation promotes GIST proliferation, growth and oxidative phosphorylation. Spatially and temporally separated GISTs from individual patients demonstrate complex tumor heterogeneity in metastatic GISTs. Finally, four prominent subtypes are proposed with different genomic features, expression profiles, immune characteristics, clinical characteristics and subtype-specific treatment strategies. This large-scale analysis depicts the landscape and provides further insights into GIST pathogenesis and precise treatment.

Advances in Small-Molecule C-KIT/PDGFRα Inhibitors for the Treatment of Gastrointestinal Stromal Tumors

AbstractStem cell factor receptor (C-KIT) or platelet-derived growth factor receptor α (PDGFRα) gene mutations have been identified as oncogenic drivers for most gastrointestinal stromal tumors (GISTs). Thus, small-molecule inhibitors of C-KIT or PDGFRα have emerged as effective treatments for GISTs. Although the currently approved first- to fourth-line drugs are initially effective against GISTs, the inevitable development of drug resistance remains an unmet challenge. To address secondary mutations leading to drug resistance, several novel selective C-KIT/PDGFRα small-molecule inhibitors have been developed and clinically studied. This review summarizes the pathogenesis, treatment, and drug resistance mechanisms of GISTs and briefly describes current challenges and future efforts for GIST treatment using small-molecule kinase inhibitors.

Iodothyronine Deiodinase 3 Gene Expression in Gastrointestinal Stromal Tumors: A Pilot Study to Contribute to Risk Assessment.

In the realm of gastrointestinal stromal tumors (GIST), understanding the molecular landscape and prognostic factors is crucial for effective management. The deiodinase 3 gene (DIO3), known for its role in thyroid hormone regulation and cell proliferation, has emerged as a potential player in GIST pathogenesis. Our study investigated DIO3 expression in GIST samples and its correlation with tumor characteristics, aiming to enhance prognostic stratification and personalized treatment strategies. Using a retrospective design, we analyzed data and formalin-fixed paraffin-embedded (FFPE) samples of patients diagnosed with GIST. The study cohort comprised 33 patients, predominantly female, with a median age of 66 years. The tumor characteristics were meticulously documented, including location, size, mitotic count, risk classification, and immunohistochemical markers. Gene expression analysis of DIO3 was conducted using FFPE samples, with a focus on relative quantification and association with immunohistochemical markers and prognostic risk. DIO3 overexpression was observed in 69.70% of tumors, while underexpression was noted in 30.30% of cases. Association analyses revealed intriguing insights. A notable association was identified between DIO3 expression and the frequency of DOG1, suggesting a potential interplay between these markers in GIST pathobiology. Furthermore, increased DIO3 expression was significantly higher in very low/low-risk prognostic patients, hinting at a possible link between DIO3 levels and tumor progression prognosis. The intricate interplay between DIO3 expression and GIST characteristics uncovered in this study underscores the potential of molecular markers in refining prognostic assessments and therapeutic strategies for GIST patients.

Morphological, immunohistochemical, and genetic analyses of epithelioid gastrointestinal stromal tumors

Epithelioid gastrointestinal stromal tumors (GISTs) are rare and may be confused with other tumors with epithelioid morphology. Therefore, herein, we collected 12 epithelioid GIST samples and summarized their morphological and immunohistochemical characteristics. Through genetic testing, we explored the correlation between morphology and gene mutations. The results showed that eight tumors showed focal or diffuse myxoid stromal changes with less cohesively arranged rhabdoid tumor cells; among these, five showed platelet-derived growth factor receptor alpha gene (PDGFRA) mutations. Signet ring cells with sclerosing stroma and receptor tyrosine kinase type III gene (KIT) mutations were present in two cases, which might be a KIT mutation-associated growth pattern in epithelioid GISTs. Succinate dehydrogenase gene (SDH) mutations were detected in three cases. Simultaneously, PDGFRA mutations were detected in two cases, and the Kirsten rat sarcoma viral oncogene homolog gene (KRAS) mutation was detected in another case. SDH-subunit B (SDHB) expression was partially weak and strongly diffuse in two cases with concurrent PDGFRA and SDHD mutations, respectively. The coexistence of PDGFRA and SDHD mutations may have affected SDHB expression. Altogether, we concluded that PDGFRA mutations may play an important role in co-mutant GIST pathogenesis.

Embryonic stem cell factor FOXD3 (Genesis) defects in gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms, believed to originate from the interstitial cells of Cajal (ICC), often caused by overexpression of tyrosine kinase receptors (TKR) KIT or PDGFRA. Here, we present evidence that the embryonic stem cell factor FOXD3, first identified as 'Genesis' and involved in both gastrointestinal and neural crest cell development, is implicated in GIST pathogenesis; its involvement is investigated both in vitro and in zebrafish and a mouse model of FOXD3 deficiency. Samples from a total of 58 patients with wild-type GISTs were used for molecular analyses, including Sanger sequencing, comparative genomic hybridization, and methylation analysis. Immunohistochemistry and western blot evaluation were used to assess FOXD3 expression. Additionally, we conducted in vitro functional studies in tissue samples and in transfected cells to confirm the pathogenicity of the identified genetic variants. Germline partially inactivating FOXD3 sequence variants (p.R54H and p.Ala88_Gly91del) were found in patients with isolated GISTs. Chromosome 1p loss was the most frequent chromosomal abnormality identified in tumors. In vitro experiments demonstrate the impairment of FOXD3 in the presence of those variants. Animal studies showed disruption of the GI neural network and changes in the number and distribution in the ICC. FOXD3 suppresses KIT expression in human cells; its inactivation led to an increase in ICC in zebrafish, as well as mice, providing evidence for a functional link between FOXD3 defects and KIT overexpression leading to GIST formation.

ETV1 inhibition depressed M2 polarization of tumor-associated macrophage and cell process in gastrointestinal stromal tumor via down-regulating PDE3A.

M2-type polarization of tumor associated-macrophage (TAM) is involved in the malignancy of gastrointestinal stromal tumor (GIST) progression. ETS variant 1 (ETV1) has been previously validated to regulate GIST pathogenesis. Our study intended to explore the role and mechanism of ETV1 in mediating the M2-polarization of TAM in GIST progression. First, we analyzed the correlation between ETV1 expression and M2-polarization in GIST tissues. IL-4 was used to treat THP-1-derived TAM cells and IL-4-stimulated TAM were co-cultured with GIST-T1 cells to mimic the GIST microenvironment. A loss-of-function assay was performed to explore the role of ETV1. Results showed that ETV1 elevation was positively correlated with M2-polarization. IL-4-induced TAM promoted ETV1 expression, silencing ETV1 inhibited proliferation, invasion and KIT activation in IL-4-treated GIST cells, while cell apoptosis was enhanced. Besides, co-culture of ETV1-silenced GIST cells significantly depressed M2-polarization in TAM, presented as decreased levels of CD206, Agr-1 and cytokines, as well as the proportion of CD206-positive TAM. PDE3A was positively correlated with ETV1 and M2-polarization. Overexpressing PDE3A reversed the inhibitory effects of ETV1 silencing. Generally, ETV1 inhibition depressed M2-polarization of TAM in GIST and its promotion on pathological aggravation via down-regulating PDE3A. This evidence may provide a new target for GIST regulation.

Genetic mutations in the molecular pathogenesis of gastrointestinal stromal tumor

Gastrointestinal stromal tumors are mesenchymal tumors which predominantly originate from the interstitial cells of Cajal in the intestinal lining. Around ~85% of malignant GISTs possess activating mutations in the tyrosine kinase receptors KIT or PDGFRA. The driver mutations in genes other than KIT or PDGFRA account for around 15% GISTs and belong to highly heterogeneous groups called wild-type GISTs. Around 20–40% of WT-GISTS are deficient for the succinate dehydrogenase complex (SDHA, SDHB, SDHC, SDHD). Mutations in SDH cause the accumulation of oncometabolite succinate that increases the level of HIF1α which enhances the transcription of several genes including IGF1, IGF2, and VEGF inducing the proliferation of the cancer cells. The remaining WT-GISTS are associated with mutations in BRAF, loss-of-function of NF1, hyperactivation FGFR, inactivation of tumor suppressor genes (p53 and dystrophin), and mutations in DNA damage response genes such as RAD51 and BRCA2 which results in the activation of the PI3K/mTOR or RAS/RAF/MAPK signaling cascade. Therefore, understanding the mutational status and molecular characterization of GIST plays a very crucial role in the overall management of GIST.

97P Development of a cas9-expressing gastrointestinal stromal tumor cell line T1-1M-R

Gastrointestinal stromal tumors (GIST) are the most frequent mesenchymal malignancies of the gastrointestinal tract. Pathogenesis of GIST is mostly associated with KIT tyrosine kinase gene mutations. Therefore, tyrosine kinases inhibitor imatinib mesylate (Gleevec) is the first-line GIST treatment. Nevertheless, GIST patients are facing secondary resistance to imatinib within 2 years of ongoing treatment. One of the possible mechanisms related to imatinib resistance is the FGF/FGFR autocrine loop, thus, FGF and FGFR might be prospective targets for imatinib-resistant GIST treatment.

Molecular Pathogenesis of Gastrointestinal Stromal Tumor: A Paradigm for Personalized Medicine.

Over the past three to four decades, the molecular pathogenesis of gastrointestinal stromal tumors (GISTs) has been elucidated in great detail. In this review, we discuss the biological genesis of GISTs, identification of the various primary activating driver mutations (focusing on KIT and PDGFRA), oncogene addiction and targeted therapies with imatinib and other tyrosine kinase inhibitors, and the subsequent characterization of the various mechanisms of drug resistance. We illustrate how GIST has become a quintessential paradigm for personalized medicine.

An Integrated Epigenome and Transcriptome Analysis to Clarify the Effect of Epigenetic Inhibitors on GIST.

Epigenetic alterations play an important role in the pathogenesis of gastrointestinal stromal tumors (GISTs). To obtain further insight into the GIST epigenome, we analyzed genome-wide histone modification and DNA methylation in GIST cells. To reverse epigenetic silencing, GIST-T1 cells were treated with a DNA methyltransferase inhibitor and a histone deacetylase inhibitor, and subsequently H3K4me3 levels, the DNA methylome, and the transcriptome were analyzed. Treatment with epigenetic inhibitors not only up-regulated genes with DNA methylation, but also genes related to interferon signaling. ChIP-seq analysis revealed that drug treatment up-regulated H3K4me3 levels in retrotransposons, including endogenous retroviruses (ERV). Finally, utilizing the omics data, we found that hypermethylation of MEG3 is a frequent event and an indicator of poorer prognosis in GIST patients. Epigenetic inhibitors may activate interferon signaling via viral mimicry in GIST cells. Moreover, epigenome data could be a useful resource to identify novel GIST-related genes.

Rare Occurrence of Microsatellite Instability in Gastrointestinal Stromal Tumors.

Background and Objectives: This study aimed to objectively determine microsatellite instability (MSI) status using a next-generation sequencing (NGS)-based MSI panel and to resolve the discrepancy regarding whether or not MSI is a rare phenomenon, irrespective of diverse genomic alterations in gastrointestinal stromal tumors (GISTs). Materials and Methods: Genomic DNA was subjected to MSI panel sequencing using an Ion AmpliSeq Microsatellite Instability Assay, as well as to cancer gene panel sequencing using an Oncomine Focus DNA Assay. Results: All of our GIST patients showed microsatellite-stable (MSS) status, which confirmed that MSI status did not affect the molecular pathogenesis of GIST. The KIT gene (79%, 38/48) was the most frequently mutated gene, followed by the PDGFRA (8%, 4/48), PIK3CA (8%, 4/48), and ERBB2 (4%, 2/48) mutations. KIT exon 11 mutant patients were more favorable in responding to imatinib than those with exon 9 mutant or wild-type GISTs, and compared to non-KIT exon 11 mutant GISTs (p = 0.041). The NGS-based MSI panel with MSICall confirmed a rare phenomenon of microsatellite instability in GISTs irrespective of diverse genomic alterations. Conclusion: Massively parallel sequencing can simultaneously provide the MSI status as well as the somatic mutation profile in a single test. This combined approach may help us to understand the molecular pathogenesis of GIST carcinogenesis and malignant progression.

Loss of SFRP1 expression is a key progression event in gastrointestinal stromal tumor pathogenesis

The mechanism of high-grade transformation in gastrointestinal stromal tumors (GISTs) remains to be clarified. We aim to discover the key progression events by studying biphasic GISTs. The study group included 101 GISTs. Nineteen of these had been screened from 263 GISTs to represent the early stage of GIST high-grade transformation, characterized by juxtaposed low-grade and high-grade regions in the same tumor (so-called biphasic GISTs). Mutational analyses, fluorescence in situ hybridization (FISH), NanoString analyses, telomere analysis, and gene expression profiling were carried out, followed by in silico analyses, cell line study, and immunohistochemical validation. Using gene expression analysis, downregulation of SFRP1 was revealed to be the main event in GIST high-grade transformation (p=0.013), accompanied by upregulation of EZH2. In silico analyses revealed that downregulation of SFRP1 was a common feature in GIST progression across several different series. Immunohistochemically, the expression of SFRP1 was validated to be significantly lower in high-grade GISTs (WHO risk group 3a or higher) than in low-grade GISTs (p<0.001), and attenuation/loss of SFRP1 was associated with GIST tumor progression (p<0.001). By NanoString and FISH analyses, chromosomal 9/9p loss was the only recurrent large-scale chromosome aberration in biphasic GISTs, with a correlation with SFRP1 downregulation. Subclones containing chromosome 9/9p loss could be appreciated in the low-grade parts of biphasic GISTs. TP53 mutation, RB1 loss, KIT/PDGFRA mutation, and alternative lengthening of telomeres did not play a significant role in GIST high-grade transformation. In conclusion, high-grade transformation of GISTs features SFRP1 downregulation and chromosome 9/9p loss.

Non-Coding RNAs, a Novel Paradigm for the Management of Gastrointestinal Stromal Tumors.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal malignancies found in the gastrointestinal tract. At a molecular level, most GISTs are characterized by gain-of-function mutations in V-Kit Hardy–Zuckerman 4 Feline Sarcoma Viral Oncogene Homolog (KIT) and Platelet Derived Growth Factor Receptor Alpha (PDGFRA), leading to constitutive activated signaling through these receptor tyrosine kinases, which drive GIST pathogenesis. In addition to surgery, treatment with the tyrosine kinase inhibitor imatinib forms the mainstay of GIST treatment, particularly in the advanced setting. Nevertheless, the majority of GISTs develop imatinib resistance. Biomarkers that indicate metastasis, drug resistance and disease progression early on could be of great clinical value. Likewise, novel treatment strategies that overcome resistance mechanisms are equally needed. Non-coding RNAs, particularly microRNAs, can be employed as diagnostic, prognostic or predictive biomarkers and have therapeutic potential. Here we review which non-coding RNAs are deregulated in GISTs, whether they can be linked to specific clinicopathological features and discuss how they can be used to improve the clinical management of GISTs.

Primary Gastrointestinal Stromal Tumor of the Prostate: Unexpected Guest.

Primary mesenchymal lesions of the prostate are exceptionally rare. They comprise 1% of all prostatic neoplasms. Despite its rare location, the diagnosis of primary gastrointestinal stromal tumors (GISTs) of the prostate gland should never be missed. Such a diagnosis can be made after the rolling out of direct extension from adjacent organs, especially the rectum. GIST diagnosis has a clinical impact on patient treatment and clinical outcomes. They harbor a certain KIT activation mutation that responds to pharmacologic therapy inhibitors.The objective of the current study was to provide a thorough review of GIST arising primarily in the prostate gland along with a comprehensive study of GIST pathogenesis, histologic morphology, immunohistochemistry, and molecular studies’ findings, and their importance in differentiating GIST from other prostate mesenchymal tumors. This will emphasize the role of careful spindle cell lesion diagnosis in the prostate gland that can influence the prognostic stratification of clinical management, future follow-up, and disease outcome.Thirteen cases were collected after an extensive and detailed review of the English literature through PubMed, Medknow, Google Scholar, as well as personal experience.The anatomic location of this lesion plays a significant role in the differential diagnosis. It is difficult to establish the accurate primary origin of GIST on core needle tissue biopsy. Thus, clinical, and radiological examinations play a crucial role in rolling out the possibility of rectal GIST secondarily invading and involving the prostate gland.To conclude, primary prostatic GIST is a rare diagnosis. Extraintestinal, particularly rectal, GIST can clinically and radiologically mimic the impression of the prostatic lesion. Before diagnosing primary prostatic spindle cell lesions, such as solitary fibrous tumor (SFT), inflammatory myofibroblastic tumor (IMT), leiomyoma, leiomyosarcoma, or prostatic stromal tumors, one should include CD117/c-Kit in the workup of a prostatic spindle cell lesion. GIST has distinct pathogenesis, and its diagnosis can have a clinical impact on the patient's management plan and clinical outcome.

The Role of miR-375-3p and miR-200b-3p in Gastrointestinal Stromal Tumors.

Deregulated microRNA (miRNA) expression profiles and their contribution to carcinogenesis have been observed in virtually all types of human cancer. However, their role in the pathogenesis of rare mesenchymal gastrointestinal stromal tumors (GISTs) is not well defined, yet. In this study, we aimed to investigate the role of two miRNAs strongly downregulated in GIST—miR-375-3p and miR-200b-3p—in the pathogenesis of GIST. To achieve this, miRNA mimics were transfected into GIST-T1 cells and changes in the potential target gene mRNA and protein expression, as well as alterations in cell viability, migration, apoptotic cell counts and direct miRNA–target interaction, were evaluated. Results revealed that overexpression of miR-375-3p downregulated the expression of KIT mRNA and protein by direct binding to KIT 3′UTR, reduced GIST cell viability and migration rates. MiR-200b-3p lowered expression of ETV1 protein, directly targeted and lowered expression of EGFR mRNA and protein, and negatively affected cell migration rates. To conclude, the present study identified that miR-375-3p and miR-200b-3p have a tumor-suppressive role in GIST.

Role of non-coding RNAs in pathogenesis of gastrointestinal stromal tumors

Role of non-coding RNAs in pathogenesis of gastrointestinal stromal tumors

Clinical significance of the molecular heterogeneity of gastrointestinal stromal tumors and related research: A systematic review.

Gastrointestinal stromal tumors (GISTs) are the most commonly observed mesenchymal tumors of the digestive tract, and they originate from the interstitial cells of Cajal. GISTs can be divided into KIT/PDGFRA‑mutant GISTs and wild‑type GISTs based on the presence or absence of KIT/PDGFRA mutations. Wild‑type GISTs can be divided into succinate dehydrogenase complex (SDH)‑deficient GISTs and non‑SDH‑deficient GISTs. Downstream signaling pathways activated by these mutations serve a pivotal role in the development of GISTs and are associated with the biological behavior, including risk stratification, clinical prognosis and drug resistance. Accurate medical care requires accurate molecular diagnosis, which in turn prolongs the survival of patients with GISTs and makes GIST a chronic disease. At present, there is a lack of effective treatment for imatinib/sunitinib/regorafenib resistant patients and KIT/PDGFRA‑WT GISTs, which is undoubtedly a major challenge for future research. The present review summarizes the molecular pathogenesis of GISTs and the progress of related research.

The shift of the treatment strategy of gastrointestinal stromal tumor from the surgical perspective

As tumors originated from mesenchymal tissue, gastrointestinal stromal tumors (GIST) has its own typical history. For the idea of treatment for GIST at different historical periods, the role and value of surgery for the treatment of GIST keep changing. Laparoscopy and endoscopy will have the role they deserved. With the understanding of pathogenesis of GIST, targeted chemotherapy will be more and more accurate and individualized. How to improve the overall therapeutic effect of GIST, especially for the patients with the high risk and drug-resistance, is the dilemma and challenges for the surgeons.

Association of Papillary Thyroid Carcinoma with GIST-a Case Series.

Gastrointestinal stromal tumours (GIST) are the most common gastrointestinal mesenchymal tumours of the gastrointestinal tract. They are diagnosed by the expression of markers like CD 117, CD 34, DOG-1 and PDGFRA. The identification of these mutations has resulted in a better understanding of their oncogenic mechanisms. Few studies have shown the high incidence of a second malignancy including papillary thyroid cancer (PTC) in known patients of GIST. Literature review on pathogenesis of GIST and PTC showed that PTC targeting Protein Kinase C theta (PKCθ) plays role in both PTC and GIST. Further studies have also shown that, apart from somatic and familial gastrointestinal stromal tumours, PDGFRA is associated with many other malignancies including PTC. These studies explain the common genetic pathway involved in the development of GIST and PTC in same patient. In spite of common genetic association between GIST and other malignancies, none of the standard protocols recommends screening for second malignancy. In this article, we present the details of four patients who had associated GIST and PTC at the same time or developed during follow-up.

Genomic aberrations in cell cycle genes predict progression of KIT-mutant gastrointestinal stromal tumors (GISTs)

BackgroundActivating mutations of the receptor tyrosine kinase KIT are early events in the development of most gastrointestinal stromal tumors (GISTs). Although GISTs generally remain dependent on oncogenic KIT during tumor progression, KIT mutations alone are insufficient to induce malignant behavior. This is evidenced by KIT-mutant micro-GISTs, which are present in up to one-third of normal individuals, but virtually never progress to malignancy.MethodsWe performed whole exome sequencing on 29 tumors obtained from 21 patients with high grade or metastatic KIT-mutant GIST (discovery set). We further validated the frequency and potential prognostic significance of aberrations in CDKN2A/B, RB1, and TP53 in an independent series of 71 patients with primary GIST (validation set).ResultsUsing whole exome sequencing we found significant enrichment of genomic aberrations in cell cycle-associated genes (Fisher’s Exact p = 0.001), most commonly affecting CDKN2A/B, RB1, and TP53 in our discovery set. We found a low mutational tumor burden in these 29 advanced GIST samples, a finding with significant implications for the development of immunotherapy for GIST. In addition, we found mutation of spliceosome genes in a minority of cases, implicating dysregulation of splicing as a potential cancer promoting mechanism in GIST. We next assessed the prognostic significance of CDKN2A, RB1 or TP53 mutation/copy loss in an independent cohort of 71 patients with primary GIST. Genetic events (mutation, deletion, and/or LOH) involving at least one of the three genes examined were found in 17% of the very low-risk, 36% of the low-risk, 42% of the intermediate risk, 67% of the high-risk/low mitotic-count, and in 86% of the high-risk/high mitotic-count group. The presence of cell cycle-related events was associated with a significantly shorter relapse-free survival (median 67 months versus not reached; p < 0.0001) and overall survival (Log Rank, p = 0.042).ConclusionOur results demonstrate that genomic events targeting cell cycle-related genes are associated with GIST progression to malignant disease. Based on this data, we propose a model for molecular pathogenesis of malignant GIST.