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Project description:The cellular context that integrates upstream signaling and downstream nuclear response dictates the oncogenic behavior and shapes treatment responses in distinct cancer types. Here, we uncover that in gastrointestinal stromal tumor (GIST), the forkhead family member FOXF1 directly controls the transcription of two master regulators, KIT and ETV1, both required for GIST precursor-interstitial cells of Cajal lineage specification and GIST tumorigenesis. Further, FOXF1 colocalizes with ETV1 at enhancers and functions as a pioneer factor that regulates the ETV1-dependent GIST lineage-specific transcriptome through modulation of the local chromatin context, including chromatin accessibility, enhancer maintenance, and ETV1 binding. Functionally, FOXF1 is required for human GIST cell growth in vitro and murine GIST tumor growth and maintenance in vivo The simultaneous control of the upstream signaling and nuclear response sets up a unique regulatory paradigm and highlights the critical role of FOXF1 in enforcing the GIST cellular context for highly lineage-restricted clinical behavior and treatment response.Significance: We uncover that FOXF1 defines the core-regulatory circuitry in GIST through both direct transcriptional regulation and pioneer factor function. The unique and simultaneous control of signaling and transcriptional circuitry by FOXF1 sets up an enforced transcriptional addiction to FOXF1 in GIST, which can be exploited diagnostically and therapeutically. Cancer Discov; 8(2); 234-51. ©2017 AACR.See related commentary by Lee and Duensing, p. 146This article is highlighted in the In This Issue feature, p. 127.
| S-EPMC5809271 | biostudies-literature
Project description:FOXF1 defines the core-regulatory circuitry in gastrointestinal stromal tumor (GIST)
| PRJNA417469 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2010-10-14 | GSE22852 | GEO
Project description:Gastrointestinal stromal tumors (GISTs) are rare tumors that can arise anywhere in the tubular gastrointestinal tract. These tumors occasionally present as a pelvic mass, leading to a misdiagnosis of gynecological disease. A 47-year-old woman presented with a pelvic mass measuring 30 cm in diameter and highly elevated CA-125 levels. She underwent exploratory laparotomy with resection of the pelvic mass. The mass mimicking ovarian malignancy was found in the sigmoid colon and was correctly diagnosed as a GIST at surgery. It should be noted that preoperative diagnosis of GIST is uncommon, due to its rarity and the varying clinical presentation. However, non-gynecological tumors should be included in the differential diagnosis of a pelvic mass with atypical presentation. Gynecologists need to be cognizant of extra-ovarian pathology in patients presenting with an atypical pelvic mass.
| S-EPMC3859154 | biostudies-other
Project description:The discovery of CD117 mutation in almost all gastrointestinal stromal tumors (GISTs) marked a milestone. Other spindle cell neoplasms arising from the GI tract including lipoma, schwannoma, hemangioma, leiomyoma, and leiomyosarcoma are typically CD117-negative. GIST research and clinical care now represent a paradigm of translating discoveries in the molecular pathogenesis of cancer into highly effective targeted therapies that selectively inhibit etiologic "driver" pathways, leading to dramatically improved clinical outcomes. A series of investigations and trials are underway to develop novel and effective ways to treat patients with GIST. In this review, we discuss the highlights of recent advances and novel agents for GIST therapy.
| S-EPMC3405472 | biostudies-literature
Project description:IntroductionGastrointestinal Stromal Tumors (GIST) are rare mesenchymal neoplasm of gastrointestinal tract. Stomach is the most common site affected by GIST compared to other places in gastrointestinal track. The coexistence of GIST with another malignancy represents a rare phenomenon with few literature reported.Case presentationWe present here 65 years old patient with stomach GIST and synchronous pancreatic adenocarcionoma discovered during surgery for suspected pancreatic mucinious cystadenoma. Distal pancreaticosplenectomy with excision of GIST Tumor & wedge resection of stomach was done. Histopathological examination of resected specimens reported the margins are clear.DiscussionIn this article we discuss on the option of systemic therapy versus upfront surgery and their outcome benefit based on literature review.ConclusionThe coexistence of GIST with pancreatic adenocarcinoma is a rare condition. High clinical analysis needed during laparotomy for GIST to detect a synchronous tumor. In a case of GIST the surgeon should recognize the possibility of another tumor with different histological origin. Surgical excision is the mainstay of therapy and it has proven to be curative for our patient. . Due to its rare occurrence and limited literature further studies has to be done on GIST with other synchronous tumor to help the surgeon to manage the patient optimally.
| S-EPMC9142392 | biostudies-literature
Project description:To clarify aberrantly expressed miRNAs affecting the biology of GIST, miRNA array was performed in 19 cases of GIST.
2013-03-01 | GSE36087 | GEO
Project description:To clarify aberrantly expressed miRNAs affecting the biology of GIST, miRNA array was performed in 19 cases of GIST. A series of 19 GISTs specimens were analyzed using 3D-Gene Human miRNA Oligo chips containing 904 human miRNAs and 107 viral miRNAs anti-sense probes printed in duplicate spots (Toray, Kamakura, Japan).
2013-03-01 | E-GEOD-36087 | biostudies-arrayexpress
Project description:BACKGROUND:Gastrointestinal stromal tumor (GIST) is the most common primary mesenchymal neoplasm of the gastrointestinal tract. Mutations of KIT and platelet-derived growth factor receptor alpha have been well characterized in GISTs. Patients with KIT mutations are generally sensitive to treatment with tyrosine kinase inhibitors. However, some patients with GIST, while initially sensitive to TKIs, gain resistance in later stages of treatment. Heterologous rhabdomyomsarcomatous dedifferentiation of advanced GISTs after long-term imatinib mesylate (IM) therapy has been reported. In these cases, the underlying molecular mechanism of tumor progression and transformation is unclear. CASE PRESENTATION:We report one such patient with rhabdomyosarcomatous dedifferentiation of a GIST without metastatic disease after brief 3-month therapy with IM. The tumor was composed of two distinct phenotypes, a CD117 negative region with rhabdomyosarcomatous differentiation directly adjacent to a CD117 positive classic GIST region. Molecular analysis identified the activating KIT exon 11 mutation in both regions, indicating a common origin for both phenotypes. Additionally, the dedifferentiated component contained two synonymous variants in platelet-derived growth factor receptor alpha and KIT. The increased number of synonymous variants in the rhabdomyosarcomatous region may reflect increased genetic instability of this tumor that may have resulted in the loss of CD117 expression in the dedifferentiated component. CONCLUSION:This study adds to the growing consensus that rhabdomyosarcomatous GIST progresses from a common GIST primary tumor. The role of IM in this progression is uncertain; however short duration of IM treatment in this study supports the hypothesis that rhabdomyosarcomatous GIST progression is not a consequence of IM therapy. Furthermore, we provide additional information supporting the observation that CD117 negative rhabdomyosarcomatous transformation maintains the activating KIT variant without KIT expression.
| S-EPMC6743131 | biostudies-literature
Project description:Although gastrointestinal stromal tumors (GISTs) harboring activating KIT or platelet-derived growth factor receptor A (PDGFRA) mutations respond to treatment with targeted KIT/PDGFRA inhibitors such as imatinib mesylate, these treatments are rarely curative. Most often, a sizeable tumor cell subpopulation survives and remains quiescent for years, eventually resulting in acquired resistance and treatment failure. Here, we report that imatinib induces autophagy as a survival pathway in quiescent GIST cells. Inhibiting autophagy, using RNAi-mediated silencing of autophagy regulators (ATGs) or antimalarial lysosomotrophic agents, promotes the death of GIST cells both in vitro and in vivo. Thus, combining imatinib with autophagy inhibition represents a potentially valuable strategy to promote GIST cytotoxicity and to diminish both cellular quiescence and acquired resistance in GIST patients.
| S-EPMC2922542 | biostudies-literature