Targeting Disease Persistence in Gastrointestinal Stromal Tumors

Ördög, Tamás; Zörnig, Martin; Hayashi, Yujiro

doi:10.5966/sctm.2014-0298

Cited by 10 publications

(17 citation statements)

References 62 publications

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“…1 GISTs arise from the interstitial cell of Cajal lineage within the enteric nervous system. 2 Approximately 70% to 80% of all sporadic GISTs have activating genomic alterations in KIT , whereas 5% to 10% have activating genomic alterations in PDGFRA . 3,4 Of the remaining GISTs, 10% to 15% have activation of the Ras pathway ( K/H/N-RAS , BRAF , NF1 ); 2% arise from mutations or deficiencies in the succinate dehydrogenase (SDH) subunits (A, B, C, or D); and a subset occurs as a result of kinase fusions ( ETV6-NTRK3 , FGFR1-TACC1 , or FGFR1-HOOK3 ) or additional mutations in genes, including ARID1A and ARID1B .…”

Section: Introductionmentioning

confidence: 99%

Duodenal-Jejunal Flexure GI Stromal Tumor Frequently Heralds Somatic NF1 and Notch Pathway Mutations

Burgoyne

Siena

Alkhuziem

et al. 2017

JCO Precision Oncology

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Purpose GI stromal tumors (GISTs) are commonly associated with somatic mutations in KIT and PDGFRA. However, a subset arises from mutations in NF1, most commonly associated with neurofibromatosis type 1. We define the anatomic distribution of NF1 alterations in GIST. Methods We describe the demographic/clinicopathologic features of 177 patients from two institutions whose GISTs underwent next-generation sequencing of ≥315 cancer-related genes. Results We initially identified six (9.7%) of 62 GISTs with NF1 genomic alterations from the first cohort. Of these six patients, five (83.3%) had unifocal tumors at the duodenal-jejunal flexure (DJF). Two additional patients with DJF GISTs had non-NF1 (KIT and BRAF) genomic alterations. After excluding one DJF GIST with an NF1 single nucleotide polymorphism, four (57.1%) of seven sequenced DJF tumors demonstrated deleterious NF1 alterations, whereas only one (1.8%) of 55 sequenced non-DJF GISTs had a deleterious NF1 somatic mutation (P < .001). One patient with DJF GIST had a germline NF1 variant that was associated with incomplete penetrance of clinical neurofibromatosis type 1 features along with a somatic NF1 mutation. Of the five DJF GISTs with any NF1 alteration, three (60%) had KIT mutations, and three (60%) had Notch pathway mutations (NOTCH2, MAML2, CDC73). We validated these findings in a second cohort of 115 GISTs, where two (40%) of five unifocal NF1-mutated GISTs arose at the DJF, and one of these also had a Notch pathway mutation (EP300). Conclusion Broad genomic profiling of adult GISTs has revealed that NF1 alterations are enriched in DJF GISTs. These tumors also may harbor concurrent activating KIT and/or inactivating Notch pathway mutations. In some cases, germline NF1 genetic testing may be appropriate for patients with DJF GISTs.

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Section: Introductionmentioning

confidence: 99%

Duodenal-Jejunal Flexure GI Stromal Tumor Frequently Heralds Somatic NF1 and Notch Pathway Mutations

Burgoyne

Siena

Alkhuziem

et al. 2017

JCO Precision Oncology

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“…In rare cases, GIST lack a mutant KIT or PDGFRA allele. These tumors may arise from mutations in KIT/PDGFRA signaling intermediates (e.g., NF1, BRAF, KRAS, HRAS ) or deficiency in the mitochondrial succinate dehydrogenase (SDH) complex caused by inactivating SDH subunit (A-D) mutations or epigenetic repression [ 2 , 3 , 8 , 9 ]. Despite their molecular heterogeneity, most GIST share common characteristics, including expression and activation of KIT and PDGFRA.…”

Section: Introductionmentioning

confidence: 99%

“…[ 17 ] SHH, PTCH1, SMO, and GLI1 expression were detected by immunohistochemistry in one study [ 18 ], and chromosome 7p amplification was found to be associated with increased GLI3 expression [ 19 ]. Interestingly, GLI3 has been reported to repress KIT mRNA levels in ICC-like cells of the murine ureter [ 20 ], raising the possibility that GLI3 may contribute to the formation of a KIT low/− GIST cell pool [ 4 ] responsible, in part, for disease persistence during imatinib therapy [ 3 ]. Additionally, conditional PTCH1 inactivation in lysozyme M-expressing murine cells has been reported to lead to the development of PDGFRA + GIST-like lesions [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

Hedgehog pathway dysregulation contributes to the pathogenesis of human gastrointestinal stromal tumors via GLI-mediated activation of KIT expression

et al. 2016

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Gastrointestinal stromal tumors (GIST) arise within the interstitial cell of Cajal (ICC) lineage due to activating KIT/PDGFRA mutations. Both ICC and GIST possess primary cilia (PC), which coordinate PDGFRA and Hedgehog signaling, regulators of gastrointestinal mesenchymal development. Therefore, we hypothesized that Hedgehog signaling may be altered in human GIST and controls KIT expression. Quantitative RT-PCR, microarrays, and next generation sequencing were used to describe Hedgehog/PC-related genes in purified human ICC and GIST. Genetic and pharmacologic approaches were employed to investigate the effects of GLI manipulation on KIT expression and GIST cell viability. We report that Hedgehog pathway and PC components are expressed in ICC and GIST and subject to dysregulation during GIST oncogenesis, irrespective of KIT/PDGFRA mutation status. Using genomic profiling, 10.2% of 186 GIST studied had potentially deleterious genomic alterations in 5 Hedgehog-related genes analyzed, including in the PTCH1 tumor suppressor (1.6%). Expression of the predominantly repressive GLI isoform, GLI3, was inversely correlated with KIT mRNA levels in GIST cells and non-KIT/non-PDGFRA mutant GIST. Overexpression of the 83-kDa repressive form of GLI3 or small interfering RNA-mediated knockdown of the activating isoforms GLI1/2 reduced KIT mRNA. Treatment with GLI1/2 inhibitors, including arsenic trioxide, significantly increased GLI3 binding to the KIT promoter, decreased KIT expression, and reduced viability in imatinib-sensitive and imatinib-resistant GIST cells. These data offer new evidence that genes necessary for Hedgehog signaling and PC function in ICC are dysregulated in GIST. Hedgehog signaling activates KIT expression irrespective of mutation status, offering a novel approach to treat imatinib-resistant GIST.

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“…8 However, resistance to imatinib mesylate is increasing and complete remission is rare, highlighting the necessity to improve our molecular understanding of GIST pathophysiology. 5 Cell dedifferentiation is a central mechanism in the initiation of neoplastic transformation and therapeutic resistance. [9][10][11] It involves loss of lineage-specific gene expression and regression from a specialized tissue to a more primitive state of development through expression of genes that govern embryonic cell-fate specification.…”

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confidence: 99%

LIX1 regulates YAP activity and controls gastrointestinal cancer cell plasticity

Guérin

Martire

Trenquier

et al. 2020

J Cellular Molecular Medi

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Gastrointestinal stromal tumours (GISTs), the most common mesenchymal neoplasm of the gastrointestinal tract, result from deregulated proliferation of transformed KIT‐positive interstitial cells of Cajal that share mesenchymal progenitors with smooth muscle cells. Despite the identification of selective KIT inhibitors, primary resistance and relapse remain a major concern. Moreover, most patients develop resistance partly through reactivation of KIT and its downstream signalling pathways. We previously identified the Limb Expression 1 ( LIX1 ) gene as a unique marker of digestive mesenchyme immaturity. We also demonstrated that LIX1 regulates mesenchymal progenitor proliferation and differentiation by controlling the Hippo effector YAP1, which is constitutively activated in many sarcomas. Therefore, we wanted to determine LIX1 role in GIST development. We found that LIX1 is strongly up‐regulated in GIST samples and this is associated with unfavourable prognosis. Moreover, LIX1 controls GIST cell proliferation in vitro and in vivo. Upon LIX1 inactivation in GIST cells, YAP1/TAZ activity is reduced, KIT (the GIST signature) is down‐regulated, and cells acquire smooth muscle lineage features. Our data highlight LIX1 role in digestive mesenchyme‐derived cell‐fate decisions and identify this novel regulator as a target for drug design for GIST treatment by influencing its differentiation status.

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Targeting Disease Persistence in Gastrointestinal Stromal Tumors

Cited by 10 publications

References 62 publications

Duodenal-Jejunal Flexure GI Stromal Tumor Frequently Heralds Somatic NF1 and Notch Pathway Mutations

Duodenal-Jejunal Flexure GI Stromal Tumor Frequently Heralds Somatic NF1 and Notch Pathway Mutations

Hedgehog pathway dysregulation contributes to the pathogenesis of human gastrointestinal stromal tumors via GLI-mediated activation of KIT expression

LIX1 regulates YAP activity and controls gastrointestinal cancer cell plasticity

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