Progression Of Gastrointestinal Stromal Tumors Research Articles

MicroRNA-128 acts as a suppressor in the progression of gastrointestinal stromal tumor by targeting B-lymphoma Mo-MLV insertion region 1.

The critical role of microRNA-128 (miR-128) in gastrointestinal-related diseases has been documented. In the current study, we tried to clarify the specific role miR-128 in gastrointestinal stromal tumor (GIST) and the underlying mechanism. Differentially expressed genes in GIST were identified following bioinformatics analysis. Then, expression patterns of miR-128 and B-lymphoma Mo-MLV insertion region 1 (BMI-1) in clinical tissue samples and cell lines were characterized, followed by validation of their correlation. GIST-T1 cells were selected and transfected with different mimic, inhibitor, or siRNA plasmids, after which the biological functions were assayed. We identified low miR-128 and high BMI-1 expression in GIST tissues of 78 patients and 4 GIST cell lines. Ectopic expression of miR-128 or silencing of BMI-1 suppressed the malignant potentials of GIST-T1 cells. As a target of miR-128, BMI-1 re-expression could partly counteract the suppressive effect of miR-128 on the malignancy of GIST-T1 cells. Our study provided evidence that miR-128-mediated silencing of BMI-1 could prevent malignant progression of GIST, highlighting a promising anti-tumor target for combating GIST.

CT features combined with RECIST 1.1 criteria improve progression assessments of sunitinib-treated gastrointestinal stromal tumors.

To explore the auxiliary value of combining CT features with existing response evaluation criteria in the prediction of progressive disease (PD) in gastrointestinal stromal tumors (GIST) patients treated with sunitinib. Eighty-one patients with GISTs who received sunitinib were included in this retrospective multicenter study and divided into training and external validation cohorts. Progression at six months was determined as a reference standard. The predictive performance of the RECIST 1.1 and Choi criteria was compared. CT features at baseline and the first follow-up were analyzed. Logistic regression analyses were used to determine the most significant predictors and develop modified criteria. A total of 216 lesions showed a good response and 107 showed a poor response in 81 patients. The RECIST 1.1 criteria performed better than the Choi criteria in predicting progression (AUC, 0.75 vs. 0.69, p= 0.04). The expanded/intensified high-enhancement area, blurred tumor-tissue interface, and progressive enlarged vessels feeding or draining the mass (EVFDM) differed significantly between lesions with good and poor responses in the training cohort (p= 0.001, 0.003, and 0.000, respectively). Multivariate analysis revealed that the expanded/intensified high-enhancement area (p= 0.001), progressive EVFDM (p= 0.000), and RECIST PD (p= 0.000) were independent predictive factors. Modified RECIST (mRECIST) criteria were developed and showed significantly higher AUCs in the training and external validation cohorts than the RECIST 1.1 criteria (training: 0.81 vs. 0.73, p= 0.002; validation: 0.82 vs. 0.77, p= 0.04). The mRECIST criteria, combining CT features with the RECIST 1.1 criteria, demonstrated superior performance in the prediction of early progression in GIST patients receiving sunitinib. The mRECIST criteria, which combine CT features with the RECIST 1.1 criteria, may facilitate the early detection of progressive disease in GIST patients treated with sunitinib, thereby potentially guiding the timely switch to late-line medications or combination with surgical excision. • The RECIST 1.1 criteria outperformed the Choi criteria in identifying progression of GISTs in patients treated with sunitinib. • GISTs displayed different morphologic features on CT depending on how they responded to sunitinib. • Combining CT morphologic features with the RECIST 1.1 criteria allowed for the prompt and accurate identification of progressing GIST lesions.

MicroRNA-409-5p Inhibits GIST Tumorigenesis and Improves Imatinib Resistance by Targeting KDM4D Expression.

Gastrointestinal stromal tumors (GISTs) can rapidly proliferate through angiogenesis. Previous studies indicated the potential influence of microRNA on the progression of tumor immature angiogenesis. This study aimed to explore the specific mechanism by which microRNA-409-5p (miR-409-5p) contributes to GIST. To identify genes potentially involved in the development and progression of GIST, the differences of miR-409-5p between tumors and adjacent tissues were first analyzed. Following this analysis, target genes were predicted. To further investigate the function of miRNA in GIST cells, two GIST cell lines (GIST-T1 and GIST882) were transfected with lentiviruses that stably expressed miR-409-5p and scrambled miRNA (negative control). Later, the cells were subjected to Western blotting and ELSA to determine any differences in angiogenesis-related genes. In GISTs, there was a decrease in the expression levels of miR-409-5p compared to the adjacent tissues. It was observed that the upregulation of miR-409-5p in GIST cell lines effectively inhibited the proteins hypoxia-inducible transcription factor 1β (HIF1β) and vascular endothelial growth factor A (VEGF-A). Further investigations revealed that miR-409-5p acted as an inhibitor of angiogenesis by binding to the 3'-UTR of Lysine-specific demethylase 4D (KDM4D) mRNA. Moreover, the combination of miR-409-5p with imatinib enhanced its inhibitory effect on angiogenesis. This study demonstrated that the miRNA-409-5p/KDM4D/HIF1β/VEGF-A signaling pathway could serve as a novel target for the development of therapeutic strategies for the treatment of imatinib-resistance in GIST patients.

Endoscopic ultrasonographic features of submucosal lesions of upper digestive tract suspected gastrointestinal stromal tumors and their correlation with progression and pathological risk grade of the lesions

Objective: To investigate the endoscopic ultrasonographic (EUS) characteristics of submucosal lesions of upper digestive tract suspected gastrointestinal stromal tumors (GIST) and their correlation with biological behaviors and pathological risk grade of the tumors. Methods: Retrospective cohort study. The EUS findings, follow-up review, surgical treatment and pathological data of patients with suspected GIST at the Gastrointestinal Endoscopy Center of Peking University People's Hospital from January 2013 to April 2021 were collected. All samples were divided into follow-up group and treatment group based on the pathological condition and the patient's treatment intention. According to whether or not the tumor was enlarged in EUS, the follow-up group was divided into non-enlarged group and enlarged group. Paired T-test was used to compare the lesion size before and after follow-up, and logistic regression was used to analyze the risk factors of tumor enlargement. According to the treatment methods, the treatment group was further divided into endoscopic treatment group and surgical treatment group. According to the pathological results and risk grade, the treatment group was further divided into the low-risk group and the medium-risk group. The risk factors of pathological malignant risk were analyzed by logistic regression, and the tumor diameter of patients with moderate or above pathological risk was predicted by receiver operation characteristic (ROC) curve. The relationship between the findings of EUS and the progression and pathological risk of GIST were also explored. Results: Seventy-three cases including 23 males and 50 females, with an age of 58 (30-88) years, were included in the follow-up group, with a mean lesion diameter of (1.21±0.49) cm before follow-up, median follow-up interval of 33.8 months, and a lesion diameter of (1.18±0.49) cm after follow-up. There was no significant difference (all P>0.05) in lesion diameter between before and after follow-up. There was no significant difference (all P>0.05) between tumor enlargement group (18 cases, 24.7%) and non-enlargement group (55 cases, 75.3%). One hundred and thirty-eight cases, including 52 males and 86 females, with an age of 60 (19-84) years, were enrolled in the treatment group, with a mean EUS estimated diameter of (2.55±1.35) cm and pathological diameters of (3.43±2.42) cm. Ninety-five (68.8%) of these cases were pathologically confirmed as GIST while 43 cases were diagnosed as other tumor types, including 37 benign tumors and 6 malignant tumors. In multifactorial logistic regression analysis, only the increase of tumor diameter [OR (95%CI): 1.800 (1.172-2.766), P=0.007] was a risk factor for pathological intermediate or higher risk. The optimal tumor diameter for predicting pathological intermediate or higher risk using ROC curve analysis was 2.75 cm, with a sensitivity 71.4%, specificity 79.0%, Youden index 0.5 and area under ROC curve 0.807 (95%CI: 0.703-0.909). Conclusions: EUS is essential for assessing the risk of progression and malignancy of submucosal lesions of upper digestive tract suspected GIST. For lesions of small diameter, the interval of follow-up shall be relatively extended while the indication of treatment could be partially waived.

P-318 TLE3-AKR1B1 signaling axis participating in the malignant progression of gastrointestinal stromal tumor by regulating galactose metabolism

P-318 TLE3-AKR1B1 signaling axis participating in the malignant progression of gastrointestinal stromal tumor by regulating galactose metabolism

TATA-box-binding protein-associated factor 15 is a novel biomarker that promotes cell proliferation and migration in gastrointestinal stromal tumor.

Gastrointestinal stromal tumor (GIST) is a common neoplasm with high rates of recurrence and metastasis, and its therapeutic efficacy is still not ideal. There is an unmet need to find new molecular therapeutic targets for GIST. TATA-box-binding protein-associated factor 15 (TAF15) contributes to the progress of various tumors, while the role and molecular mechanism of TAF15 in GIST progression are still unknown. To explore new molecular therapeutic targets for GIST and understand the biological role and underlying mechanisms of TAF15 in GIST progression. Proteomic analysis was performed to explore the differentially expressed proteins in GIST. Western blotting and immunohistochemical analysis were used to verify the expression level of TAF15 in GIST tissues and cell lines. Cell counting kit-8, colony formation, wound-healing and transwell assay were executed to detect the ability of TAF15 on cell proliferation, migration and invasion. A xenograft mouse model was applied to explore the role of TAF15 in the progression of GIST. Western blotting was used to detect the phosphorylation level and total level of RAF1, MEK and ERK1/2. A total of 1669 proteins were identified as differentially expressed proteins with 762 upregulated and 907 downregulated in GIST. TAF15 was selected for the further study because of its important role in cell proliferation and migration. TAF15 was significantly over expressed in GIST tissues and cell lines. Overexpression of TAF15 was associated with larger tumor size and higher risk stage of GIST. TAF15 knockdown significantly inhibited the cell proliferation and migration of GIST in vitro and suppressed tumor growth in vivo. Moreover, the inhibition of TAF15 expression significantly decreased the phosphorylation level of RAF1, MEK and ERK1/2 in GIST cells and xenograft tissues, while the total RAF1, MEK and ERK1/2 had no significant change. TAF15 is over expressed in GIST tissues and cell lines. Overexpression of TAF15 was associated with a poor prognosis of GIST patients. TAF15 promotes cell proliferation and migration in GIST via the activation of the RAF1/MEK/ERK signaling pathway. Thus, TAF15 is expected to be a novel latent molecular biomarker or therapeutic target of GIST.

Wnt Signaling in the Gastrointestinal Tract in Health and Disease

Wnt signaling involves multiple pathways that contribute to organ development, cell fate, inflammation, and normal stem cell renewal and maintenance. Although the homeostasis of stem cells in the gastrointestinal (GI) tract highly depends on the Wnt signaling pathway, this regulation is impaired in cancers and in aging. Overactive (uncontrolled) Wnt signaling can induce GI epithelial cancers such as colon and gastric cancer. Overactive Wnt signaling can also contribute to the initiation and progression of gastrointestinal stromal tumor, which is the most common human sarcoma occurring in the walls of the digestive organs, mainly the stomach and small intestine. Wnt expression is positively associated not only with the progression of oncogenesis but also with resistance to chemotherapy and radiotherapy. Of note, recent reports show that decreased Wnt signaling is related to intestinal stem cell aging and that overactivated Wnt signaling leads to gastric pacemaker stem cell aging in tunica muscularis. These findings indicate that Wnt signaling has different crucial aspects of cell fate determination with age in GI tunica mucosa and muscularis. In this review, we summarize the most recent advances in our understanding of Wnt signaling pathways and their role in regulating key aspects during development, carcinogenesis, inflammation, and aging, with the ultimate goal of identifying novel therapies.

ADRB2 Regulates the Proliferation and Metastasis of Gastrointestinal Stromal Tumor Cells by Enhancing the ETV1-c-KIT Signaling.

Gastrointestinal stromal tumor (GIST) originates from a pacemaker cell, the Cajal cell. However, little is known about the cancer neuroscience in GIST. In this study, we aimed to elucidate the clinical and biological roles of adrenoceptor beta 2 (ADRB2) in GIST. Immunohistochemistry was used to evaluate the expression of ADRB2 in GIST tissues. The biological effects of ADRB2 on GIST cell proliferation, migration, invasion, and apoptosis were explored using Cell Counting Kit -8, plate colony formation assay, transwell invasion assay, and flow cytometry. We also explored the growth and metastasis of xenograft tumors in nude mice. Western blotting was used to quantify protein expression and phosphorylation. ADRB2 is generally highly expressed in GIST. High ADRB2 expression was significantly associated with risk level, tumor size, mitotic count, and metastasis. Overexpression of ADRB2 promoted GIST cell proliferation, migration, invasion, and apoptosis, while silencing ADRB2 expression showed the opposite effects. Furthermore, we found that silencing endogenous ADRB2 inhibited GIST progression and metastasis in nude mice. ADRB2-induced ETV1 upregulation enhanced the activation of c-KIT. ADRB2 plays an important role in the proliferation and metastasis of GIST and is expected to be a potential target for the treatment of GIST.

Prognostic significance of serum CA125 in the overall management for patients with gastrointestinal stromal tumors

BackgroundCarbohydrate antigen 125 (CA125) is elevated as a tumor marker in many carcinomas, but its association with gastrointestinal stromal tumor (GIST) has received less attention. This study intends to evaluate whether CA125 level can predict tumor progression and overall survival (OS) of GIST patients.MethodsWe retrospectively analyzed the clinical data and follow-up records of GIST patients who underwent surgical resection in Nanjing Drum Tower Hospital from August 2010 to December 2020. All patients were classified according to serum CA125 level. The relationship between CA125 and clinical outcomes was then examined.ResultsA total of 406 GIST patients were enrolled in this study, among which 46 patients had preoperative elevated serum CA125 level and 13 patients with high CA125 level both preoperative and postoperative were observed. Preoperative CA125 concentration was significantly related to rupture status, resection style, tumor site, tumor size, mitotic index, NIH risk grade and c-kit exons. According to Kaplan–Meier curve analysis, high expression of postoperative CA125 was significantly correlated with worse progression-free survival (PFS) and OS among patients with preoperative elevated CA125 level. Ultimately, Cox proportional regression model analysis revealed that increase of preoperative and concurrent postoperative CA125 concentration was an independent predictive factor for PFS.ConclusionsThe concurrent abnormality of serum CA125 before and after operation was an independent risk factor for GIST progression, suggesting its significance as a serum biomarker in the overall management of GIST patients.

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.

The Prognostic Value of Plasma Small Extracellular Vesicles' Phenotype in Patients With Gastrointestinal Stromal Tumor.

For patients with local gastrointestinal stromal tumor (GIST), risk stratification is used to assess the prognosis and identify patients to offer adjuvant treatment. For patients with advanced or metastatic GIST, no such risk stratification exists. This study aimed to investigate the prognostic value of 31 different plasma small extracellular vesicles' (SEVs) surface proteins in GIST patients. GIST patients from the two sarcoma centers in Denmark were included. Patients were divided into three groups; group 1: patients undergoing radical surgery; group 2: patients with local, locally advanced, or metastatic GIST; and group 3: patients without evidence of disease after radical surgery. Protein microarray technology was used for the analysis of plasma SEVs. The median plasma SEV marker level was used when comparing groups of patients. The primary endpoint was the progression of GIST. Iterative statistical modeling was used to identify a SEV marker profile/model with a prognostic value. A total of 157 patients were included, with a median follow-up time of 2.05 years. In group 2, a high level of carcinoembryonic antigen (CEA) and a low level of glucose transporter 1 (GLUT-1) were found to be poor prognostic factors [univariate analysis; GLUT-1: hazard ratio (HR)=0.47, 95% confidence interval (CI)=0.22-0.98; CEA: HR=2.12, 95%CI=1.02-4.44]. Composing a model consisting of CEA and GLUT-1 adjusted for age at inclusion was found to have a prognostic value (HR=4.93, 95%CI=2.30-10.57, p<0.0001). Plasma SEVs in GIST showed that CEA and GLUT-1 might be of prognostic value. However, external validation is needed.

Advances in the research of the mechanism of secondary resistance to imatinib in gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. At present, surgery is the first-line treatment for primary resectable GISTs; however, the recurrence rate is high. Imatinib mesylate (IM) is an effective first-line drug used for the treatment of unresectable or metastatic recurrent GISTs. More than 80% of patients with GISTs show significantly improved 5-year survival after treatment; however, approximately 50% of patients develop drug resistance after 2 years of IM treatment. Therefore, an in-depth research is urgently needed to reveal the mechanisms of secondary resistance to IM in patients with GISTs and to develop new therapeutic targets and regimens to improve their long-term prognoses. In this review, research on the mechanisms of secondary resistance to IM conducted in the last 5 years is discussed and summarized from the aspects of abnormal energy metabolism, gene mutations, non-coding RNA, and key proteins. Studies have shown that different drug-resistance mechanism networks are closely linked and interconnected. However, the influence of these drug-resistance mechanisms has not been compared. The combined inhibition of drug-resistance mechanisms with IM therapy and the combined inhibition of multiple drug-resistance mechanisms are expected to become new therapeutic options in the treatment of GISTs. In addition, implementing individualized therapies based on the identification of resistance mechanisms will provide new adjuvant treatment options for patients with IM-resistant GISTs, thereby delaying the progression of GISTs. Previous studies provide theoretical support for solving the problems of drug-resistance mechanisms. However, most studies on drug-resistance mechanisms are still in the research stage. Further clinical studies are needed to confirm the safety and efficacy of the inhibition of drug-resistance mechanisms as a potential therapeutic target.

Methyltransferase-like 3 (METTL3) mediated N6-methyladenosine (m6A) modifications facilitate mir-25-3p maturation to promote gastrointestinal stromal tumors (GISTs) progression.

Methyltransferase-like 3 (METTL3) is an RNA N6-methyladenosine (m6A) methyltransferase, which plays a critical role in micorRNA (miRNAs) processing and maturation, but it is still unclear whether METTL3 regulated miRNAs participates in the regulation of cancer aggressiveness in gastrointestinal stromal tumors (GISTs). This study was designed to investigate this issue, and uncover the potential underlying mechanisms. the expression of METTL3 in GISTs tissues and cell lines were determined by RT-qPCR and Western blot. Cell proliferation and migration were assessed by colony formation, CCK-8 and Transwell. The mRNA expression of all proteins was detected by RT-qPCR, and tumor xenograft study was applied to confirm the effect of METTL3 on GISTs development in vivo. In our study, we showed that METTL3 was significantly upregulated in GISTs tissues and cell lines. Functional experiments demonstrated that overexpression of METTL3 promoted GISTs cell malignant biological behavior and tumor growth in vitro and in vivo, and conversely, silencing of METTL3 had opposite effects and suppressed GISTs progression. Further mechanistical experiments verified that METTL3 promoted the maturation of miR-25-3p in an m6A-dependent manner. Similar to METTL3, miR-25-3p was also validated as an oncogene to promote cancer development in GISTs. Finally, our rescuing experiments hinted that silencing of miR-25-3p abrogated the tumor-initiating effects of METTL3 overexpression on GISTs. Collectively, those results indicated that METTL3 played an oncogenic role in GISTs through positively modulating the miR-25-3p in an m6A-dependent manner, and we firstly discussed how the METTL3/m6A/miR-25-3p axis affected GISTs development.

Angiogenesis in gastrointestinal stromal tumors: From bench to bedside

Gastrointestinal stromal tumors (GISTs) are rare neoplasms with an estimated incidence from 0.78 to 1-1.5 patients per 100000. They most commonly occur in the elderly during the eighth decade of life affecting predominantly the stomach, but also the small intestine, the omentum, mesentery and rectosigmoid. The available treatments for GIST are associated with a significant rate of recurrent disease and adverse events. Thorough understanding of GIST’s pathophysiology and translation of this knowledge into novel regimens or drug repurposing is essential to counter this challenge. The present review summarizes the existing evidence about the role of angiogenesis in GIST’s development and progression and discusses its clinical underpinnings.

SMYD2 aggravates gastrointestinal stromal tumor via upregulation of EZH2 and downregulation of TET1

SMYD2, as an oncogene, has been involved in multiple types of cancer, but the potential role of SMYD2 in gastrointestinal stromal tumors (GIST) remains enigmatic and requires further investigation. Hence, this study was conducted with the main objective of analyzing the effect of SMYD2 on GIST. GIST and adjacent normal tissues were collected from 46 patients with GIST where the expression of EZH2, SMYD2, and TET1 was determined, followed by the analysis of their interactions. The functional role of SMYD2 in cell biological functions was determined using a loss-of-function assay in GIST-T1 cells. Nude mouse xenograft experiments were performed to verify the role of the SMYD2/EZH2/TET1 axis in GIST in vivo. EZH2 was upregulated in GIST tissues and cell lines, which was positively correlated with SMYD2 expression and inversely correlated with TET1 expression in GIST tissues. EZH2 silencing due to SMYD2 inhibition reduced GIST-T1 cell proliferation and accelerated cell senescence. EZH2 repressed TET1 expression by promoting H3K27me3 methylation in the TET1 promoter region. TET1 inhibition reversed the effect of EZH2 silencing on the biological functions of GIST-T1 cells. In vivo data further revealed the promoting effect of SMYD2 on the progression of GIST by regulating the EZH2/TET1 axis. Overall, this study demonstrates that SMYD2 can increase EZH2 expression while suppressing TET1 expression, thus accelerating GIST, and creating new treatment opportunities for GIST.

CTCF-activated SNHG16 facilitates gastrointestinal stromal tumor by targeting miR-128-3p/CASC3 axis

In this study, it was ascertained that SNHG16 was up-regulated in gastrointestinal stromal tumor (GIST) tissues and cells, and was responsible for the aggravated malignant behaviors of GIST cells. CTCF served as a transcription activator responsible for the overexpression of SNHG16 in GIST cells. MiR-128-3p was negatively regulated by SNHG16 and exerted anti-tumor effects. Moreover, CASC3 was the direct target mRNA of miR-128-3p, through which miR-128-3p exerted function influence on GIST cell malignant behaviors. SNHG16 competitively bound with miR-128-3p against CASC3, thus positively regulating CASC3 expression. Finally, functional assays carried out in vitro proved SNHG16 could modulate GIST cell proliferation, migration, invasion and apoptosis via miR-128-3p/CASC3 axis. Animal experiments were also designed and implemented in a rescue way and evidenced that up-regulation of CASC3 countervailed the inhibitory impacts of SNHG16 silence on the progression of GIST. In summary, SNHG16 up-regulated by CTCF facilitated the progression of GIST through miR-128-3p/CASC3.

The Diagnosis of Small Gastrointestinal Subepithelial Lesions by Endoscopic Ultrasound-Guided Fine Needle Aspiration and Biopsy.

Endoscopic ultrasonography (EUS) has been widely accepted in the diagnosis of all types of tumors, especially pancreatic tumors, lymph nodes, and subepithelial lesions (SELs). One reason is that the examination can provide a detailed observation, with tissue samples being immediately obtained by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). Many SELs are detected incidentally during endoscopic examinations without symptoms. Most SELs are mesenchymal tumors originating from the fourth layer, such as gastrointestinal stromal tumors (GISTs), leiomyomas, and schwannomas. GISTs are potentially malignant. Surgical treatment is recommended for localized GISTs of ≥20 mm. However, the indications for the diagnosis and follow-up of GISTs of <20 mm in size are controversial. There are several reports on the rapid progression or metastasis of small GISTs. Therefore, it is important to determine whether a SEL is a GIST or not. The main diagnostic method is EUS-FNA. Recently, endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) using a new biopsy needle has been reported to obtain larger tissue samples. Additionally, various biopsy methods have been reported to have a high diagnostic rate for small GISTs. In local gastric SELs, regardless of the tumor size, EUS can be performed first; then, EUS-FNA/B or various biopsy methods can be used to obtain tissue samples for decision-making in relation to therapy and the follow-up period.

Imatinib-associated skin rash is related to treatment outcome in patients with unresectable and/or metastatic gastrointestinal stromal tumor.

Imatinib-associated skin rash in gastrointestinal stromal tumor (GIST) patients is one of the most troublesome adverse effects, and can reduce imatinib adherence and persistence. However, the relationship between skin rash and adherence is unknown, and there are few published studies on the clinical outcomes of patients with severe skin rash. Adult patients (≥18 years) who were treated with 400 mg/day imatinib for unresectable or metastatic GIST were enrolled in this retrospective study. The skin rash was graded by physicians according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Progression-free survival (PFS) was compared using the Kaplan-Meier method between groups with and without skin rash. The risk factors for GIST progression were investigated by Cox regression analysis. A total of 125 GIST patients were finally included. Among them, 43 (34.4%) patients developed skin rash during imatinib treatment. Serial blood eosinophil levels were associated with skin rash and severity (P<0.001). Patients with skin rash tended to have poorer PFS than patients with no rash (P=0.035). Moreover, patients with rash had a significantly higher prevalence of non-adherence compared with patients without rash [odds ratio (OR): 3.42, 95% confidence interval (CI): 1.36-8.61, P=0.009 for grades 1-2; OR: 6.07, 95% CI: 1.42-26.11, P=0.015 for grades 3-4). Cox regression analysis indicated that the independent risk factors for GIST progression were non-adherence (OR: 4.20, 95% CI: 1.57-11.25, P=0.004) and medium- and high-risk GIST (OR: 5.38, 95% CI: 1.15-25.09, P=0.032). Non-adherence and medium- and high-risk GIST are independent risk factors for GIST progression. Skin rash can be associated with treatment adherence, which can in turn be associated with poor outcomes of GIST treatment. Measuring the blood eosinophil levels could be helpful in predicting risk of skin rash during imatinib treatment.

Identification of New Tumor-Related Gene Mutations in Chinese Gastrointestinal Stromal Tumors.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. As the main GIST drivers, gain-of-function mutations in KIT or PDGFRA are closely associated with not only tumor development and progression but also therapeutic response. In addition to the status of KIT and PDGFRA, little is known about other potential GIST-related genes. In this study, we identified the mutation profiles in 49 KIT-mutated GIST tumors using the whole exome sequencing (WES) method. Furthermore, some representative mutations were further validated in an independent GIST cohort using the SNaPshot SNP assay. We identified extensive and diverse mutations of KIT in GIST, including many undescribed variants. In addition, we revealed some new tumor-related gene mutations with unknown pathogenicity. By enrichment analyses of gene function and protein-protein interaction network construction, we showed that these genes were enriched in several important cancer- or metabolism-related signaling pathways, including PI3K-AKT,RTK-RAS, Notch, Wnt, Hippo, mTOR, AMPK, and insulin signaling. In particular, DNA repair-related genes, including MLH1, MSH6, BRCA1, BRCA2, and POLE, are frequently mutated in GISTs, suggesting that immune checkpoint blockade may have promising clinical applications for these GIST subpopulations. In conclusion, in addition to extensive and diverse mutations of KIT, some genes related to DNA-repair and cell metabolism may play important roles in the development, progression and therapeutic response of GIST.

BRD9 inhibition promotes PUMA-dependent apoptosis and augments the effect of imatinib in gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GISTs) are primarily characterized by activating mutations of tyrosine kinase or platelet-derived growth factor receptor alpha. Although the revolutionary therapeutic outcomes of imatinib are well known, the long-term benefits of imatinib are still unclear. The effects of BRD9, a recently identified subunit of noncanonical BAF complex (ncBAF) chromatin remodeling complexes, in GISTs are not clear. In the current study, we evaluated the functional role of BRD9 in GIST progression. Our findings demonstrated that the expression of BRD9 was upregulated in GIST tissues. The downregulation or inhibition of BRD9 could significantly reduce cellular proliferation, and facilitates apoptosis in GISTs. BRD9 inhibition could promote PUMA-dependent apoptosis in GISTs and enhance imatinib activity in vitro and in vivo. BRD9 inhibition synergizes with imatinib in GISTs by inducing PUMA upregulation. Mechanism study revealed that BRD9 inhibition promotes PUMA induction via the TUFT1/AKT/GSK-3β/p65 axis. Furthermore, imatinib also upregulates PUMA by targeting AKT/GSK-3β/p65 axis. In conclusion, our results indicated that BRD9 plays a key role in the progression of GISTs. Inhibition of BRD9 is a novel therapeutic strategy in GISTs treated alone or in combination with imatinib.