Materiały źródłowe

• #1 Gastrointestinal Stromal Tumors (GISTs): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/278845-overview

  Gastrointestinal stromal tumors (GISTs) account for less than 1% of GI tumors, but they are the most common mesenchymal neoplasms of the GI tract. […] According to the work of Kindblom and associates, reported in 1998, the actual cell of origin of GISTs is a pluripotential mesenchymal stem cell programmed to differentiate into the interstitial cell of Cajal. […] Additional studies found that interstitial cells of Cajal express KIT and are developmentally dependent on stem cell factor, which is regulated through KIT kinase. […] Perhaps the most critical development that distinguished GISTs as a unique clinical entity was the discovery of c-KIT proto-oncogene mutations in these tumors in by Hirota and colleagues in 1998. […] Activating KIT mutations are seen in 85-95% of GISTs. […] The PDGFR alpha mutation seems to leave the PDGFRalpha receptor constitutively active and may represent an alternate pathway with activation of similar downstream signaling as the KIT receptor.

• #2 Gastrointestinal stromal tumor pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Gastrointestinal_stromal_tumor_pathophysiology

  Gastrointestinal stromal tumors (GISTs) are rare but the most common mesenchymal (nonepithelial) tumors of the gastrointestinal tract. […] Genes involved in the pathogenesis of gastrointestinal stromal tumors include mutations in c-Kit gene and PDGFRA (platelet derived growth factor receptor-alpha) gene. Both Kit gene and PDGFRA are tyrosine kinase receptors and control cell proliferation. Mutation in c-Kit gene and PDGFRA leads to inhibition of apoptosis and uncontrolled cell proliferation. […] Molecular analysis has shown that GISTs arising from the interstitial cells of Cajal, stain positive for CD117 (c-KIT) in 90% cases and CD34 in 70% of cases. […] The most commonly observed mutation site in c-Kit gene involves exon 11 leading to a gain-of-function mutation. […] Gain of function mutation leads to overexpression and autophosphorylation of c-Kit that leads to inhibition of apoptosis and uncontrolled cell proliferation. […] About 10% cases of GIST are associated with PDGFRA gene. […] As a result of mutation, the PDGFRA gene gets activated on its own and leads to inhibition of apoptosis and uncontrolled cell proliferation.

• #3 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Gastrointestinal-Stromal-Tumor-Pathogenesis.aspx

  Gastrointestinal stromal tumors (GISTs) are soft-tissue sarcomas found in the digestive system, commonly occurring in the stomach and small intestine. The tumor arises from specialized nerve cells, which are also part of the autonomous nervous system, found in the walls of the gastrointestinal tract. […] Usually, a change or mutation in the DNA of one of the cells may lead to the development of GIST. These cells aid in the movement of food through the intestines and control of various digestive processes. The activating mutations of KIT or the platelet-derived growth factor receptor alpha gene (PDGFRA) have been linked to the development of GISTs. […] How does gastrointestinal stromal tumor develop? The possible root cause of GIST is the genetic change in one of several genes. Approximately 80 percent of cases are linked to the mutation in the KIT gene. At the same time, about 10 percent of cases involved mutations in the PDGFRA gene.

• #4 Molecular characterization and pathogenesis of gastrointestinal stromal tumor

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5803009/

  Most gastrointestinal stromal tumors (GISTs) harbor activating mutations in the receptor tyrosine kinase gene KIT or platelet-derived growth factor receptor alpha (PDGFRA), and the resultant activation of downstream signals plays a pivotal role in the development of GISTs. […] Activating mutations in the receptor tyrosine kinase gene KIT or platelet-derived growth factor receptor alpha (PDGFRA) play essential roles in the pathogenesis of GISTs through upregulation of downstream signaling pathways, including RAS/RAF/MAPK and PI3K/AKT/mTOR. […] Neurofibromin 1 (NF1) also acts as a tumor suppressor gene in GISTs, and patients with neurofibromatosis type I are known to be at high risk of developing multiple GISTs. […] SDH deficiency results in the accumulation of succinate, which is a competitive inhibitor of -ketoglutarate-dependent dioxygenases, including the TET family of 5-methylcytosine hydroxylases.

• #5 Molecular characterization and pathogenesis of gastrointestinal stromal tumor

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5803009/

  In fact, a genome-wide DNA methylation analysis of SDH-deficient GISTs revealed greater DNA hypermethylation than in GISTs with KIT mutation. […] Accumulation of succinate is also involved in the stabilization of HIF1-, which controls oncogene transcription. […] GISTs with no mutations in KIT, PDGFRA or RAS pathway genes or SDH-deficiency are referred as wild-type GISTs. […] Within GISTs, KIT mutations are found in several gene regions, including exons 8, 9, 11, 13, 14, 15, and 17. […] Approximately 10% to 15% of GISTs exhibit PDFRA mutations. […] These mutations are found in exon 12 (juxtamembrane domain), exon 14 (ATP binding domain), and exon 18 (activation loop), and cause constitutive PDGFRA activation in the absence of ligand binding, leading to downstream activation of signaling pathways.

• #6 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Gastrointestinal-Stromal-Tumor-Pathogenesis.aspx

  When there are mutations in the PDGFRA and KIT genes, these can cause the proteins to no longer require ligand binding to the stimulated and activated. In turn, the proteins and the signaling pathway is turned on consistently, leading to uncontrolled cell growth, and eventually, GIST development. […] Most cases of GIST are not hereditary or passed down in families. GIST has been linked to somatic mutations, which are described as genetic changes that happen only in the tumor cells, in the lifetime of a person, and not because he or she got it from the family. However, in some cases, called familial GISTs, the genetic mutations in the KIT and PDGFRA genes, mutations are passed down through an autosomal dominant pattern.

• #7 Gastrointestinal Stromal Tumors (GISTs): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/278845-overview

  Gastrointestinal stromal tumors (GISTs) account for less than 1% of GI tumors, but they are the most common mesenchymal neoplasms of the GI tract. […] According to the work of Kindblom and associates, reported in 1998, the actual cell of origin of GISTs is a pluripotential mesenchymal stem cell programmed to differentiate into the interstitial cell of Cajal. […] Additional studies found that interstitial cells of Cajal express KIT and are developmentally dependent on stem cell factor, which is regulated through KIT kinase. […] Perhaps the most critical development that distinguished GISTs as a unique clinical entity was the discovery of c-KIT proto-oncogene mutations in these tumors in by Hirota and colleagues in 1998. […] Activating KIT mutations are seen in 85-95% of GISTs. […] The PDGFR alpha mutation seems to leave the PDGFRalpha receptor constitutively active and may represent an alternate pathway with activation of similar downstream signaling as the KIT receptor.

• #8 Gastrointestinal stromal tumor – Wikipedia

  https://en.wikipedia.org/wiki/Gastrointestinal_stromal_tumor

  Gastrointestinal stromal tumors (GISTs) are defined as tumors whose behavior is driven by mutations in the KIT gene (85%), PDGFRA gene (10%), or BRAF kinase (rare). […] The understanding of GIST biology changed significantly with identification of the molecular basis of GIST, particularly c-KIT. […] Approximately 85% GISTs are associated with an abnormal c-KIT pathway. c-KIT is a gene that encodes for a transmembrane receptor for a growth factor termed stem cell factor (scf). […] Mutations make c-KIT function independent of activation by scf, leading to a high cell division rate and possibly genomic instability. […] Additional mutations are likely „required” for a cell with a c-KIT mutation to develop into a GIST, but the c-KIT mutation is probably the first step of this process. […] Mutations in the exons 11, 9 and rarely 13 and 17 of the c-KIT gene are known to occur in GIST. […] Most GIST cells with wildtype (i.e. not mutated) c-KIT instead have a mutation in another gene, PDGFR- (platelet-derived growth factor receptor alpha), which is a related tyrosine kinase. […] Lesser numbers of GISTs appear to be associated with neither c-KIT nor PDGFR- abnormalities.

• #9 Molecular characterization and pathogenesis of gastrointestinal stromal tumor

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5803009/

  In fact, a genome-wide DNA methylation analysis of SDH-deficient GISTs revealed greater DNA hypermethylation than in GISTs with KIT mutation. […] Accumulation of succinate is also involved in the stabilization of HIF1-, which controls oncogene transcription. […] GISTs with no mutations in KIT, PDGFRA or RAS pathway genes or SDH-deficiency are referred as wild-type GISTs. […] Within GISTs, KIT mutations are found in several gene regions, including exons 8, 9, 11, 13, 14, 15, and 17. […] Approximately 10% to 15% of GISTs exhibit PDFRA mutations. […] These mutations are found in exon 12 (juxtamembrane domain), exon 14 (ATP binding domain), and exon 18 (activation loop), and cause constitutive PDGFRA activation in the absence of ligand binding, leading to downstream activation of signaling pathways.

• #10 Gastrointestinal stromal tumor – Zhao – Journal of Gastrointestinal Oncology

  https://jgo.amegroups.org/article/view/434/html

  Furthermore, GISTs demonstrate typical patterns of chromosomal gains and losses, including losses at 1p, 14q, 15q, and 22q. […] KIT oncogenetic activation is the dominant pathogenetic mechanism in GIST. […] The most common mutations in KIT are found in the juxtamembrane domain that is encoded by the 5′ end of exon 11 of the KIT receptor. […] The mutations vary from in-frame deletions of variable sizes, point mutations to deletions preceded by substitutions. […] The deletions are associated with a more aggressive behavior in comparison to other exon 11 mutations. […] A less common mutant spot is located at the 3′ end of exon 11, which includes mainly internal tandem duplications mutations. […] The second most common KIT mutation, between 10% and 15% of GISTs, is a mutation in an extracellular domain encoded by exon 9.

• #11 Gastrointestinal Stromal Tumors (GISTs): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/278845-overview

  The discovery of these receptor mutations has redefined the classification and management of the disease. […] In the majority of GISTs, KIT is constitutively phosphorylated and does not require stem cell factor for initiation of the sequence of c-Kit homodimerization and autophosphorylation. This is termed ligand-independent activation. […] The increased transduction of proliferative signals to the nucleus favors cell survival and replication over dormancy and apoptosis, leading to tumorigenesis. […] Although 95% of GISTs are KIT positive, 5% of GISTs have no detectable KIT expression. […] In a proportion of these KIT-negative GISTs, mutations occur in the PDGFRA gene rather than KIT. […] BRAF mutations and protein kinase C theta (PKCtheta) have also been reported in a small proportion of GISTs lacking KIT/PDGFRA.

• #12 Molecular characterization and pathogenesis of gastrointestinal stromal tumor

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5803009/

  In fact, a genome-wide DNA methylation analysis of SDH-deficient GISTs revealed greater DNA hypermethylation than in GISTs with KIT mutation. […] Accumulation of succinate is also involved in the stabilization of HIF1-, which controls oncogene transcription. […] GISTs with no mutations in KIT, PDGFRA or RAS pathway genes or SDH-deficiency are referred as wild-type GISTs. […] Within GISTs, KIT mutations are found in several gene regions, including exons 8, 9, 11, 13, 14, 15, and 17. […] Approximately 10% to 15% of GISTs exhibit PDFRA mutations. […] These mutations are found in exon 12 (juxtamembrane domain), exon 14 (ATP binding domain), and exon 18 (activation loop), and cause constitutive PDGFRA activation in the absence of ligand binding, leading to downstream activation of signaling pathways.

• #13 Gastrointestinal stromal tumor – Zhao – Journal of Gastrointestinal Oncology

  https://jgo.amegroups.org/article/view/434/html

  In 1995 Huizinga and colleagues reported a knockout mice model of KIT failed to express in interstitial cells of Cajal cells. […] It is now established that KIT mutations, which cause the constitutive activation of the kinase, are found in 70-80% of GISTs. […] CD117 becomes a crucial diagnostic marker for GIST, and mutant KIT provides an important therapeutic target clinically in GIST treatment. […] Currently PDGFRA mutations account for 5-10% of known mutations in GIST. […] In GIST, mutant forms of PDGFRA have constitutive kinase activity in the absence of their ligand-PDGFRA similar to those for KIT mutations, and the activated downstream pathways are identical to those in KIT-mutant GISTs. […] Recent studies indicate that a small portion of GIST wild-type for both KIT and PDGFRA genes may harbor mutations of the BRAF gene and KRAS and BRAF mutations predict primary resistance to imatinib in GISTs.

• #14 Molecular characterization and pathogenesis of gastrointestinal stromal tumor

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5803009/

  In fact, a genome-wide DNA methylation analysis of SDH-deficient GISTs revealed greater DNA hypermethylation than in GISTs with KIT mutation. […] Accumulation of succinate is also involved in the stabilization of HIF1-, which controls oncogene transcription. […] GISTs with no mutations in KIT, PDGFRA or RAS pathway genes or SDH-deficiency are referred as wild-type GISTs. […] Within GISTs, KIT mutations are found in several gene regions, including exons 8, 9, 11, 13, 14, 15, and 17. […] Approximately 10% to 15% of GISTs exhibit PDFRA mutations. […] These mutations are found in exon 12 (juxtamembrane domain), exon 14 (ATP binding domain), and exon 18 (activation loop), and cause constitutive PDGFRA activation in the absence of ligand binding, leading to downstream activation of signaling pathways.

• #15 Gastrointestinal stromal tumor – Zhao – Journal of Gastrointestinal Oncology

  https://jgo.amegroups.org/article/view/434/html

  In 1995 Huizinga and colleagues reported a knockout mice model of KIT failed to express in interstitial cells of Cajal cells. […] It is now established that KIT mutations, which cause the constitutive activation of the kinase, are found in 70-80% of GISTs. […] CD117 becomes a crucial diagnostic marker for GIST, and mutant KIT provides an important therapeutic target clinically in GIST treatment. […] Currently PDGFRA mutations account for 5-10% of known mutations in GIST. […] In GIST, mutant forms of PDGFRA have constitutive kinase activity in the absence of their ligand-PDGFRA similar to those for KIT mutations, and the activated downstream pathways are identical to those in KIT-mutant GISTs. […] Recent studies indicate that a small portion of GIST wild-type for both KIT and PDGFRA genes may harbor mutations of the BRAF gene and KRAS and BRAF mutations predict primary resistance to imatinib in GISTs.

• #16 Molecular Mechanisms of Gastrointestinal Stromal – ProQuest

  https://www.proquest.com/scholarly-journals/molecular-mechanisms-gastrointestinal-stromal/docview/2785176701/se-2

  In 1998, Hirota and colleagues discovered that activating KIT mutations are the major mechanism of GIST oncogenesis. […] Activating mutations in KIT lead to the formation of a permanently active protein that is a target for imatinib binding. […] Of equal importance and the second most common driver mutations in GISTs are mutations in PDGFRA, which encodes the PDGFRA receptor tyrosine kinase. […] KIT/PDGFRA-induced oncogenesis mediates the rapidly accelerated fibrosarcoma (RAF)-mitogen-activated protein kinase (MEK)-mitogen-activated protein kinases (MAPK) (RAF-MEK-MAPK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) (PI3K-AKT) signaling pathways. […] At present, it is believed that KIT/PDGFRA-activating mutations are mutually exclusive. […] In recent years, it has been discovered that only 85-90% of GISTs have an activating mutation in KIT/PDGFRA, while in the remaining 10-15%, the molecular mechanism of oncogenesis has not been determined.

• #17 Pathology Outlines – Gastrointestinal stromal tumor (GIST)

  https://www.pathologyoutlines.com/topic/softtissueGIST.html

  Gastrointestinal stromal tumor (GIST) is a mesenchymal neoplasm with variable behavior, characterized by differentiation toward the interstitial cells of Cajal based on IHC and molecular studies. […] Specific, generally KIT or PDGFRA mutation driven mesenchymal tumor. […] Early events in GIST development are activating mutations in KIT or PDGFRA, which occur in most GISTs and encode for mutated tyrosine receptor kinases that are therapeutic targets for tyrosine kinase inhibitors (TKI), including imatinib and sunitinib. […] Majority of GISTs are sporadic. […] ~25% of GISTs are clinically malignant. […] Most common gain of function mutations in GISTs are either in the KIT (60 – 70%) or platelet derived growth factor receptor alpha (PDGFRA) genes (10 – 15%), which are mutually exclusive.

• #18 Molecular characterization and pathogenesis of gastrointestinal stromal tumor

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5803009/

  Most gastrointestinal stromal tumors (GISTs) harbor activating mutations in the receptor tyrosine kinase gene KIT or platelet-derived growth factor receptor alpha (PDGFRA), and the resultant activation of downstream signals plays a pivotal role in the development of GISTs. […] Activating mutations in the receptor tyrosine kinase gene KIT or platelet-derived growth factor receptor alpha (PDGFRA) play essential roles in the pathogenesis of GISTs through upregulation of downstream signaling pathways, including RAS/RAF/MAPK and PI3K/AKT/mTOR. […] Neurofibromin 1 (NF1) also acts as a tumor suppressor gene in GISTs, and patients with neurofibromatosis type I are known to be at high risk of developing multiple GISTs. […] SDH deficiency results in the accumulation of succinate, which is a competitive inhibitor of -ketoglutarate-dependent dioxygenases, including the TET family of 5-methylcytosine hydroxylases.

• #19 Understanding Gastric GIST: From Pathophysiology to Personalized Treatment

  https://www.mdpi.com/2077-0383/13/14/3997

  Gastric gastrointestinal stromal tumors (GISTs) represent a subset of gastrointestinal tumors predominantly found in the stomach. Despite their rarity, these tumors carry significant implications for patient health and management. GISTs are potentially malignant tumors with unpredictable progression. They originate from the interstitial cells of Cajal, which are positioned between the intramural neurons and the smooth muscle cells of the digestive tract. These tumors are characterized primarily by mutations in the c-Kit gene, as well as other mutations such as those in the platelet-derived growth factor receptor alpha (PDGFRA) gene. […] The hallmark of gastric GIST pathophysiology lies in the dysregulation of receptor tyrosine kinase (RTK) signaling pathways, primarily involving the KIT (CD117) and platelet-derived growth factor receptor alpha (PDGFRA) genes. These mutations lead to constitutive activation of downstream signaling cascades, including the RAS-RAF-MEK-ERK and PI3K-AKT-mTOR pathways, resulting in uncontrolled cellular proliferation and inhibition of apoptosis. In gastric GISTs, aberrant activation of KIT and PDGFRA promotes tumor growth and progression by stimulating cell cycle progression, enhancing angiogenesis, and facilitating evasion of immune surveillance mechanisms. Additionally, dysregulated signaling within the tumor microenvironment promotes tumor invasion and metastasis, contributing to the aggressive behavior observed in some cases.

• #20

  https://xiahepublishing.com/2310-8819/JCTH-2022-00173

  Both GISTs, and ICCs are positive for KIT and CD34, and ICCs are the only cells in the GI tract positive for both KIT and CD34. Thus, GISTs are thought to originate from ICCs. […] GIST mutations in KIT, platelet-derived growth factor receptor alpha (PDGFRA), HRAS, NRAS, BRAF, neurofibromatosis type 1 (NF1), or succinate dehydrogenase complex (SDH) have been reported. The most common of these are gain-of-function mutations in KIT and PDGFRA genes, which occur in about 8287% of mutations. […] KIT and PDGFRA genes are located on 4q12 encoding type III receptor tyrosine kinase. KIT then activates PI3K/AKT/mTOR and JAK/STAT pathways. PDGFRA activates the RAS/MAPK kinase signaling pathways, which affect cell proliferation, differentiation, migration, apoptosis, and survival. […] Understanding the mutations also helps differentiate between familial associations and primary tumor sites.

• #21 Molecular characterization and pathogenesis of gastrointestinal stromal tumor

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5803009/

  Most gastrointestinal stromal tumors (GISTs) harbor activating mutations in the receptor tyrosine kinase gene KIT or platelet-derived growth factor receptor alpha (PDGFRA), and the resultant activation of downstream signals plays a pivotal role in the development of GISTs. […] Activating mutations in the receptor tyrosine kinase gene KIT or platelet-derived growth factor receptor alpha (PDGFRA) play essential roles in the pathogenesis of GISTs through upregulation of downstream signaling pathways, including RAS/RAF/MAPK and PI3K/AKT/mTOR. […] Neurofibromin 1 (NF1) also acts as a tumor suppressor gene in GISTs, and patients with neurofibromatosis type I are known to be at high risk of developing multiple GISTs. […] SDH deficiency results in the accumulation of succinate, which is a competitive inhibitor of -ketoglutarate-dependent dioxygenases, including the TET family of 5-methylcytosine hydroxylases.

• #22 Understanding Gastric GIST: From Pathophysiology to Personalized Treatment

  https://www.mdpi.com/2077-0383/13/14/3997

  Gastric gastrointestinal stromal tumors (GISTs) represent a subset of gastrointestinal tumors predominantly found in the stomach. Despite their rarity, these tumors carry significant implications for patient health and management. GISTs are potentially malignant tumors with unpredictable progression. They originate from the interstitial cells of Cajal, which are positioned between the intramural neurons and the smooth muscle cells of the digestive tract. These tumors are characterized primarily by mutations in the c-Kit gene, as well as other mutations such as those in the platelet-derived growth factor receptor alpha (PDGFRA) gene. […] The hallmark of gastric GIST pathophysiology lies in the dysregulation of receptor tyrosine kinase (RTK) signaling pathways, primarily involving the KIT (CD117) and platelet-derived growth factor receptor alpha (PDGFRA) genes. These mutations lead to constitutive activation of downstream signaling cascades, including the RAS-RAF-MEK-ERK and PI3K-AKT-mTOR pathways, resulting in uncontrolled cellular proliferation and inhibition of apoptosis. In gastric GISTs, aberrant activation of KIT and PDGFRA promotes tumor growth and progression by stimulating cell cycle progression, enhancing angiogenesis, and facilitating evasion of immune surveillance mechanisms. Additionally, dysregulated signaling within the tumor microenvironment promotes tumor invasion and metastasis, contributing to the aggressive behavior observed in some cases.

• #23

  https://xiahepublishing.com/2310-8819/JCTH-2022-00173

  PHGIST is considered sporadic and has not been reported with familial GISTs or germ-line mutations. […] Mechanisms by which of tyrosine kinase inhibitors regulate activation of PHGIST cells. […] Receptor tyrosine kinases are a group of transmembrane tyrosine kinases involved in regulation of a wide range of complex cellular processes including growth, differentiation, and metabolism. One member of the family, KIT, can activate the JAK/STAT pathway which promotes cell proliferation, differentiation, and apoptosis. Another member, PDGFR, activates Ras/Raf pathway which leads to gene amplification and cell survival as well as apoptosis. […] As PHGISTs have the same histology and immunochemistry as GISTs, they are treated in the same way. The selective tyrosine kinase receptor inhibitor (TKI), imatinib mesylate, has been used as adjuvant or neoadjuvant therapy.

• #24 Molecular Mechanisms of Gastrointestinal Stromal – ProQuest

  https://www.proquest.com/scholarly-journals/molecular-mechanisms-gastrointestinal-stromal/docview/2785176701/se-2

  In 1998, Hirota and colleagues discovered that activating KIT mutations are the major mechanism of GIST oncogenesis. […] Activating mutations in KIT lead to the formation of a permanently active protein that is a target for imatinib binding. […] Of equal importance and the second most common driver mutations in GISTs are mutations in PDGFRA, which encodes the PDGFRA receptor tyrosine kinase. […] KIT/PDGFRA-induced oncogenesis mediates the rapidly accelerated fibrosarcoma (RAF)-mitogen-activated protein kinase (MEK)-mitogen-activated protein kinases (MAPK) (RAF-MEK-MAPK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) (PI3K-AKT) signaling pathways. […] At present, it is believed that KIT/PDGFRA-activating mutations are mutually exclusive. […] In recent years, it has been discovered that only 85-90% of GISTs have an activating mutation in KIT/PDGFRA, while in the remaining 10-15%, the molecular mechanism of oncogenesis has not been determined.

• #25 Gastrointestinal Stromal Tumors (GISTs): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/278845-overview

  The discovery of these receptor mutations has redefined the classification and management of the disease. […] In the majority of GISTs, KIT is constitutively phosphorylated and does not require stem cell factor for initiation of the sequence of c-Kit homodimerization and autophosphorylation. This is termed ligand-independent activation. […] The increased transduction of proliferative signals to the nucleus favors cell survival and replication over dormancy and apoptosis, leading to tumorigenesis. […] Although 95% of GISTs are KIT positive, 5% of GISTs have no detectable KIT expression. […] In a proportion of these KIT-negative GISTs, mutations occur in the PDGFRA gene rather than KIT. […] BRAF mutations and protein kinase C theta (PKCtheta) have also been reported in a small proportion of GISTs lacking KIT/PDGFRA.

• #26 Molecular Mechanisms of Gastrointestinal Stromal – ProQuest

  https://www.proquest.com/scholarly-journals/molecular-mechanisms-gastrointestinal-stromal/docview/2785176701/se-2

  Improved understanding of the molecular biology of the disease and the identification of driver alterations and mechanisms of resistance to systemic therapies have resulted in advances in the systemic treatment of GISTs, thereby broadening the systemic therapy armamentarium. […] Tyrosine kinase inhibitors (TKIs) represent the standard systemic therapy and comprise various targeted drugs. […] Despite the convincing achievements with TKI treatment, targeted therapy eventually leads to the development of drug resistance. Secondary mutations play a major role in this process, allowing for the selection of cells that are resistant to the treatment applied. […] The proto-oncogene KIT encodes the KIT receptor, which is a type III receptor tyrosine kinase (RTK); it belongs to a family of RTKs that also includes PDGFRA.

• #27 Gastrointestinal Stromal Tumors (GISTs): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/278845-overview

  The discovery of these receptor mutations has redefined the classification and management of the disease. […] In the majority of GISTs, KIT is constitutively phosphorylated and does not require stem cell factor for initiation of the sequence of c-Kit homodimerization and autophosphorylation. This is termed ligand-independent activation. […] The increased transduction of proliferative signals to the nucleus favors cell survival and replication over dormancy and apoptosis, leading to tumorigenesis. […] Although 95% of GISTs are KIT positive, 5% of GISTs have no detectable KIT expression. […] In a proportion of these KIT-negative GISTs, mutations occur in the PDGFRA gene rather than KIT. […] BRAF mutations and protein kinase C theta (PKCtheta) have also been reported in a small proportion of GISTs lacking KIT/PDGFRA.

• #28 Molecular characterization and pathogenesis of gastrointestinal stromal tumor

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5803009/

  In fact, a genome-wide DNA methylation analysis of SDH-deficient GISTs revealed greater DNA hypermethylation than in GISTs with KIT mutation. […] Accumulation of succinate is also involved in the stabilization of HIF1-, which controls oncogene transcription. […] GISTs with no mutations in KIT, PDGFRA or RAS pathway genes or SDH-deficiency are referred as wild-type GISTs. […] Within GISTs, KIT mutations are found in several gene regions, including exons 8, 9, 11, 13, 14, 15, and 17. […] Approximately 10% to 15% of GISTs exhibit PDFRA mutations. […] These mutations are found in exon 12 (juxtamembrane domain), exon 14 (ATP binding domain), and exon 18 (activation loop), and cause constitutive PDGFRA activation in the absence of ligand binding, leading to downstream activation of signaling pathways.

• #29 Update on Molecular Genetics of Gastrointestinal Stromal Tumors

  https://www.mdpi.com/2075-4418/11/2/194

  It is well known that approximately 80% of GISTs harbor activating mutations in the KIT or PDGFRA genes that are responsible for the up-regulation of crucial signaling pathways including MAPK and PI3K-AKT. On the other hand, GISTs lacking KIT and PDGFRA mutations are referred to as “wild-type” (wt)-GISTs. These tumors differ from KIT and PDGFRA-mutant GISTs with regard to their clinical behavior and heterogenetic molecular profile. Over the past few years, advances in molecular pathology helped to elucidate alternative molecular drivers in the non KIT- non PDGFRA- mutated so-called “wt”-GIST group. Alternative mutations, structural chromosomal and epigenetic changes have been demonstrated in this group making the molecular classification more complex. Recent insights about the crucial role of the SDH-complex, especially in the pathobiology of pediatric GISTs, helped to divide GISTs by immunohistochemistry in a succinate dehydrogenase B (SDHB)-retained and SDHB-deficient subgroup. This widely available screening approach can facilitate decisions on further molecular testing strategies.

• #30 Molecular characterization and pathogenesis of gastrointestinal stromal tumor

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5803009/

  Most gastrointestinal stromal tumors (GISTs) harbor activating mutations in the receptor tyrosine kinase gene KIT or platelet-derived growth factor receptor alpha (PDGFRA), and the resultant activation of downstream signals plays a pivotal role in the development of GISTs. […] Activating mutations in the receptor tyrosine kinase gene KIT or platelet-derived growth factor receptor alpha (PDGFRA) play essential roles in the pathogenesis of GISTs through upregulation of downstream signaling pathways, including RAS/RAF/MAPK and PI3K/AKT/mTOR. […] Neurofibromin 1 (NF1) also acts as a tumor suppressor gene in GISTs, and patients with neurofibromatosis type I are known to be at high risk of developing multiple GISTs. […] SDH deficiency results in the accumulation of succinate, which is a competitive inhibitor of -ketoglutarate-dependent dioxygenases, including the TET family of 5-methylcytosine hydroxylases.

• #31 Molecular characterization and pathogenesis of gastrointestinal stromal tumor

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5803009/

  In fact, a genome-wide DNA methylation analysis of SDH-deficient GISTs revealed greater DNA hypermethylation than in GISTs with KIT mutation. […] Accumulation of succinate is also involved in the stabilization of HIF1-, which controls oncogene transcription. […] GISTs with no mutations in KIT, PDGFRA or RAS pathway genes or SDH-deficiency are referred as wild-type GISTs. […] Within GISTs, KIT mutations are found in several gene regions, including exons 8, 9, 11, 13, 14, 15, and 17. […] Approximately 10% to 15% of GISTs exhibit PDFRA mutations. […] These mutations are found in exon 12 (juxtamembrane domain), exon 14 (ATP binding domain), and exon 18 (activation loop), and cause constitutive PDGFRA activation in the absence of ligand binding, leading to downstream activation of signaling pathways.

• #32 Molecular characterization and pathogenesis of gastrointestinal stromal tumor – Niinuma – Translational Gastroenterology and Hepatology

  https://tgh.amegroups.org/article/view/4057/html

  Recent studies have shown that epigenetic alterations and noncoding RNAs also play key roles in the pathogenesis of GISTs. […] GISTs with no mutations in KIT, PDGFRA or RAS pathway genes or SDH-deficiency are referred as wild-type GISTs. […] A subset of wild-type GISTs exhibit mutations in TP53, MEN1 or MAX, and are characterized by a neural-committed phenotype and upregulation of the master endocrine regulator ASCL1. […] Epigenetic alterations, including aberrant DNA methylation and histone modification, have also been implicated in the development of GISTs. […] Accumulation of succinate is also involved in the stabilization of HIF1-, which controls oncogene transcription. […] The IGF family consists of two ligands (IGF1 and IGF2), two receptors (IGFR1 and IGFR1) and 6 IGF binding proteins (IGFBPs), and binding of IGF and IGFR activates downstream signals, including the MAPK and PI3K/AKT pathways.

• #33 Molecular characterization and pathogenesis of gastrointestinal stromal tumor – Niinuma – Translational Gastroenterology and Hepatology

  https://tgh.amegroups.org/article/view/4057/html

  Inhibition of IGF1R induces apoptosis and represses AKT and MAPK signaling in GIST cells, which implicates the IGF signal in the development of SDH-deficient GISTs. […] Neurofibromatosis type1 is an inheritable disease caused by bi-allelic loss of the NF1 gene. […] NF1-associated GISTs do not harbor KIT/PDGFRA mutations; instead, loss of NF1 leads to MAPK signal activation, while PI3K-AKT and JAK-STAT signals are less active than in common GISTs. […] Chromosomal aberrations are prevalent among GISTs, with approximately 60% to 70% of all GISTs exhibiting alterations in chromosome 14, including loss of 14q and monosomy 14. […] In addition, nearly half of GISTs show loss of 22q, while losses of 1p, 9p, 10q, 11p, 13q, 15q and 17p are also reported with lesser frequencies. […] A number of functionally important genes are located in the regions frequently deleted in GISTs, including PARP2, APEX1, and NDRG2 at 14q11.2; SIVA at 14q32.33; MAX at 14q23.3; and NF2 at 22q12.2. […] SETD2 mutations were recently identified in high-risk and metastatic GISTs. […] Loss of SETD2 is associated with reduced H3K36me3, DNA hypomethylated heterochromatin, and significantly worse outcomes in GIST patients, which suggests SETD2 is a novel GIST tumor suppressor.

• #34 Molecular characterization and pathogenesis of gastrointestinal stromal tumor

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5803009/

  Mutations in RAS family genes and BRAF are found in a subset of GISTs. […] The BRAF V600E mutation is detected in malignant melanoma and thyroid and colorectal cancers. […] The mutant BRAF cooperates with Rac1b, AKT3 and other signal molecules to promote tumor cell viability and proliferation. […] Neurofibromatosis type1 is an inheritable disease caused by bi-allelic loss of the NF1 gene. […] Individuals with NF1 mutations are at high risk of developing GISTs. […] Chromosomal aberrations are prevalent among GISTs, with approximately 60% to 70% of all GISTs exhibiting alterations in chromosome 14, including loss of 14q and monosomy 14. […] In addition, nearly half of GISTs show loss of 22q, while losses of 1p, 9p, 10q, 11p, 13q, 15q and 17p are also reported with lesser frequencies.

• #35

  https://xiahepublishing.com/2310-8819/JCTH-2022-00173

  Both GISTs, and ICCs are positive for KIT and CD34, and ICCs are the only cells in the GI tract positive for both KIT and CD34. Thus, GISTs are thought to originate from ICCs. […] GIST mutations in KIT, platelet-derived growth factor receptor alpha (PDGFRA), HRAS, NRAS, BRAF, neurofibromatosis type 1 (NF1), or succinate dehydrogenase complex (SDH) have been reported. The most common of these are gain-of-function mutations in KIT and PDGFRA genes, which occur in about 8287% of mutations. […] KIT and PDGFRA genes are located on 4q12 encoding type III receptor tyrosine kinase. KIT then activates PI3K/AKT/mTOR and JAK/STAT pathways. PDGFRA activates the RAS/MAPK kinase signaling pathways, which affect cell proliferation, differentiation, migration, apoptosis, and survival. […] Understanding the mutations also helps differentiate between familial associations and primary tumor sites.

• #36 Gastrointestinal stromal tumor | Radiology Reference Article | Radiopaedia.org

  https://radiopaedia.org/articles/gastrointestinal-stromal-tumor-2?lang=us

  KIT (~75%) or PDGFRA (~10%) oncogene gain-of-function mutations in encoding for type III receptor tyrosine kinases. […] Many KIT and PDGFRA wildtype GISTs have SDH subunit gene alternation (5-10%) leading to a distinct subtype, „SDH-deficient GIST”, which more commonly present as gastric tumors in younger patients (particularly children) and female patients.

• #37 Syndromic gastrointestinal stromal tumors | Hereditary Cancer in Clinical Practice | Full Text

  https://hccpjournal.biomedcentral.com/articles/10.1186/s13053-016-0055-4

  SDH-deficient GISTs often behave indolently, even in case of metastases, probably due to the metabolic disadvantage caused by SDH deficiency. […] TKI imatinib and sunitinib proved ineffective or only partially effective, respectively, in SDH-deficient GISTs, coherently with SHD deficiency constituting a pathway independent of KIT/PDGFRA.

• #38 Molecular characterization and pathogenesis of gastrointestinal stromal tumor – Niinuma – Translational Gastroenterology and Hepatology

  https://tgh.amegroups.org/article/view/4057/html

  Recent studies have shown that epigenetic alterations and noncoding RNAs also play key roles in the pathogenesis of GISTs. […] GISTs with no mutations in KIT, PDGFRA or RAS pathway genes or SDH-deficiency are referred as wild-type GISTs. […] A subset of wild-type GISTs exhibit mutations in TP53, MEN1 or MAX, and are characterized by a neural-committed phenotype and upregulation of the master endocrine regulator ASCL1. […] Epigenetic alterations, including aberrant DNA methylation and histone modification, have also been implicated in the development of GISTs. […] Accumulation of succinate is also involved in the stabilization of HIF1-, which controls oncogene transcription. […] The IGF family consists of two ligands (IGF1 and IGF2), two receptors (IGFR1 and IGFR1) and 6 IGF binding proteins (IGFBPs), and binding of IGF and IGFR activates downstream signals, including the MAPK and PI3K/AKT pathways.

• #39 Molecular characterization and pathogenesis of gastrointestinal stromal tumor

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5803009/

  DNA methylation is an important mechanism for regulating gene expression, and hypermethylation of CpG islands is a major mechanism by which tumor suppressor genes are inactivated within tumor cells. […] SETD2 mutations were recently identified in high-risk and metastatic GISTs. […] Loss of SETD2 is associated with reduced H3K36me3, DNA hypomethylated heterochromatin, and significantly worse outcomes in GIST patients, which suggests SETD2 is a novel GIST tumor suppressor.

• #40 Molecular characterization and pathogenesis of gastrointestinal stromal tumor

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5803009/

  In fact, a genome-wide DNA methylation analysis of SDH-deficient GISTs revealed greater DNA hypermethylation than in GISTs with KIT mutation. […] Accumulation of succinate is also involved in the stabilization of HIF1-, which controls oncogene transcription. […] GISTs with no mutations in KIT, PDGFRA or RAS pathway genes or SDH-deficiency are referred as wild-type GISTs. […] Within GISTs, KIT mutations are found in several gene regions, including exons 8, 9, 11, 13, 14, 15, and 17. […] Approximately 10% to 15% of GISTs exhibit PDFRA mutations. […] These mutations are found in exon 12 (juxtamembrane domain), exon 14 (ATP binding domain), and exon 18 (activation loop), and cause constitutive PDGFRA activation in the absence of ligand binding, leading to downstream activation of signaling pathways.

• #41 Molecular characterization and pathogenesis of gastrointestinal stromal tumor

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5803009/

  DNA methylation is an important mechanism for regulating gene expression, and hypermethylation of CpG islands is a major mechanism by which tumor suppressor genes are inactivated within tumor cells. […] SETD2 mutations were recently identified in high-risk and metastatic GISTs. […] Loss of SETD2 is associated with reduced H3K36me3, DNA hypomethylated heterochromatin, and significantly worse outcomes in GIST patients, which suggests SETD2 is a novel GIST tumor suppressor.

• #42 Molecular characterization and pathogenesis of gastrointestinal stromal tumor – Niinuma – Translational Gastroenterology and Hepatology

  https://tgh.amegroups.org/article/view/4057/html

  Inhibition of IGF1R induces apoptosis and represses AKT and MAPK signaling in GIST cells, which implicates the IGF signal in the development of SDH-deficient GISTs. […] Neurofibromatosis type1 is an inheritable disease caused by bi-allelic loss of the NF1 gene. […] NF1-associated GISTs do not harbor KIT/PDGFRA mutations; instead, loss of NF1 leads to MAPK signal activation, while PI3K-AKT and JAK-STAT signals are less active than in common GISTs. […] Chromosomal aberrations are prevalent among GISTs, with approximately 60% to 70% of all GISTs exhibiting alterations in chromosome 14, including loss of 14q and monosomy 14. […] In addition, nearly half of GISTs show loss of 22q, while losses of 1p, 9p, 10q, 11p, 13q, 15q and 17p are also reported with lesser frequencies. […] A number of functionally important genes are located in the regions frequently deleted in GISTs, including PARP2, APEX1, and NDRG2 at 14q11.2; SIVA at 14q32.33; MAX at 14q23.3; and NF2 at 22q12.2. […] SETD2 mutations were recently identified in high-risk and metastatic GISTs. […] Loss of SETD2 is associated with reduced H3K36me3, DNA hypomethylated heterochromatin, and significantly worse outcomes in GIST patients, which suggests SETD2 is a novel GIST tumor suppressor.

• #43

  https://www.omim.org/entry/606764

  Chi et al. (2010) demonstrated that ETV1 (600541) is highly expressed in the subtypes of interstitial cells of Cajal (ICCs) sensitive to oncogenic KIT-mediated transformation, and is required for their development. In addition, ETV1 is universally highly expressed in GISTs and is required for growth of imatinib-sensitive and -resistant GIST cell lines. Transcriptome profiling and global analyses of ETV1-binding sites suggested that ETV1 is a master regulator of an ICC-GIST-specific transcription network mainly through enhancer binding. The ETV1 transcriptional program is further regulated by activated KIT, which prolongs ETV1 protein stability and cooperates with ETV1 to promote tumorigenesis. Chi et al. (2010) proposed that GIST arises from ICCs with high levels of endogenous ETV1 expression that, when coupled with an activating KIT mutation, drives an oncogenic ETS transcriptional program. This model differs from other ETS-dependent tumors such as prostate cancer, melanoma, and Ewing sarcoma where genomic translocation or amplification drives aberrant ETS expression. Chi et al. (2010) also stated that this model of GIST pathogenesis represents a novel mechanism of oncogenic transcription factor activation.

• #44

  https://www.omim.org/entry/606764

  Chi et al. (2010) demonstrated that ETV1 (600541) is highly expressed in the subtypes of interstitial cells of Cajal (ICCs) sensitive to oncogenic KIT-mediated transformation, and is required for their development. In addition, ETV1 is universally highly expressed in GISTs and is required for growth of imatinib-sensitive and -resistant GIST cell lines. Transcriptome profiling and global analyses of ETV1-binding sites suggested that ETV1 is a master regulator of an ICC-GIST-specific transcription network mainly through enhancer binding. The ETV1 transcriptional program is further regulated by activated KIT, which prolongs ETV1 protein stability and cooperates with ETV1 to promote tumorigenesis. Chi et al. (2010) proposed that GIST arises from ICCs with high levels of endogenous ETV1 expression that, when coupled with an activating KIT mutation, drives an oncogenic ETS transcriptional program. This model differs from other ETS-dependent tumors such as prostate cancer, melanoma, and Ewing sarcoma where genomic translocation or amplification drives aberrant ETS expression. Chi et al. (2010) also stated that this model of GIST pathogenesis represents a novel mechanism of oncogenic transcription factor activation.

• #45 Molecular characterization and pathogenesis of gastrointestinal stromal tumor

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5803009/

  Mutations in RAS family genes and BRAF are found in a subset of GISTs. […] The BRAF V600E mutation is detected in malignant melanoma and thyroid and colorectal cancers. […] The mutant BRAF cooperates with Rac1b, AKT3 and other signal molecules to promote tumor cell viability and proliferation. […] Neurofibromatosis type1 is an inheritable disease caused by bi-allelic loss of the NF1 gene. […] Individuals with NF1 mutations are at high risk of developing GISTs. […] Chromosomal aberrations are prevalent among GISTs, with approximately 60% to 70% of all GISTs exhibiting alterations in chromosome 14, including loss of 14q and monosomy 14. […] In addition, nearly half of GISTs show loss of 22q, while losses of 1p, 9p, 10q, 11p, 13q, 15q and 17p are also reported with lesser frequencies.

• #46 Molecular characterization and pathogenesis of gastrointestinal stromal tumor – Niinuma – Translational Gastroenterology and Hepatology

  https://tgh.amegroups.org/article/view/4057/html

  Inhibition of IGF1R induces apoptosis and represses AKT and MAPK signaling in GIST cells, which implicates the IGF signal in the development of SDH-deficient GISTs. […] Neurofibromatosis type1 is an inheritable disease caused by bi-allelic loss of the NF1 gene. […] NF1-associated GISTs do not harbor KIT/PDGFRA mutations; instead, loss of NF1 leads to MAPK signal activation, while PI3K-AKT and JAK-STAT signals are less active than in common GISTs. […] Chromosomal aberrations are prevalent among GISTs, with approximately 60% to 70% of all GISTs exhibiting alterations in chromosome 14, including loss of 14q and monosomy 14. […] In addition, nearly half of GISTs show loss of 22q, while losses of 1p, 9p, 10q, 11p, 13q, 15q and 17p are also reported with lesser frequencies. […] A number of functionally important genes are located in the regions frequently deleted in GISTs, including PARP2, APEX1, and NDRG2 at 14q11.2; SIVA at 14q32.33; MAX at 14q23.3; and NF2 at 22q12.2. […] SETD2 mutations were recently identified in high-risk and metastatic GISTs. […] Loss of SETD2 is associated with reduced H3K36me3, DNA hypomethylated heterochromatin, and significantly worse outcomes in GIST patients, which suggests SETD2 is a novel GIST tumor suppressor.

• #47 Molecular characterization and pathogenesis of gastrointestinal stromal tumor – Niinuma – Translational Gastroenterology and Hepatology

  https://tgh.amegroups.org/article/view/4057/html

  Inhibition of IGF1R induces apoptosis and represses AKT and MAPK signaling in GIST cells, which implicates the IGF signal in the development of SDH-deficient GISTs. […] Neurofibromatosis type1 is an inheritable disease caused by bi-allelic loss of the NF1 gene. […] NF1-associated GISTs do not harbor KIT/PDGFRA mutations; instead, loss of NF1 leads to MAPK signal activation, while PI3K-AKT and JAK-STAT signals are less active than in common GISTs. […] Chromosomal aberrations are prevalent among GISTs, with approximately 60% to 70% of all GISTs exhibiting alterations in chromosome 14, including loss of 14q and monosomy 14. […] In addition, nearly half of GISTs show loss of 22q, while losses of 1p, 9p, 10q, 11p, 13q, 15q and 17p are also reported with lesser frequencies. […] A number of functionally important genes are located in the regions frequently deleted in GISTs, including PARP2, APEX1, and NDRG2 at 14q11.2; SIVA at 14q32.33; MAX at 14q23.3; and NF2 at 22q12.2. […] SETD2 mutations were recently identified in high-risk and metastatic GISTs. […] Loss of SETD2 is associated with reduced H3K36me3, DNA hypomethylated heterochromatin, and significantly worse outcomes in GIST patients, which suggests SETD2 is a novel GIST tumor suppressor.

• #48 Molecular characterization and pathogenesis of gastrointestinal stromal tumor – Niinuma – Translational Gastroenterology and Hepatology

  https://tgh.amegroups.org/article/view/4057/html

  Inhibition of IGF1R induces apoptosis and represses AKT and MAPK signaling in GIST cells, which implicates the IGF signal in the development of SDH-deficient GISTs. […] Neurofibromatosis type1 is an inheritable disease caused by bi-allelic loss of the NF1 gene. […] NF1-associated GISTs do not harbor KIT/PDGFRA mutations; instead, loss of NF1 leads to MAPK signal activation, while PI3K-AKT and JAK-STAT signals are less active than in common GISTs. […] Chromosomal aberrations are prevalent among GISTs, with approximately 60% to 70% of all GISTs exhibiting alterations in chromosome 14, including loss of 14q and monosomy 14. […] In addition, nearly half of GISTs show loss of 22q, while losses of 1p, 9p, 10q, 11p, 13q, 15q and 17p are also reported with lesser frequencies. […] A number of functionally important genes are located in the regions frequently deleted in GISTs, including PARP2, APEX1, and NDRG2 at 14q11.2; SIVA at 14q32.33; MAX at 14q23.3; and NF2 at 22q12.2. […] SETD2 mutations were recently identified in high-risk and metastatic GISTs. […] Loss of SETD2 is associated with reduced H3K36me3, DNA hypomethylated heterochromatin, and significantly worse outcomes in GIST patients, which suggests SETD2 is a novel GIST tumor suppressor.

• #49

  https://journals.lww.com/otm/fulltext/2024/06000/systemic_therapy_in_gastrointestinal_stromal.3.aspx

  The MYC-associated factor X (MAX) gene, located on the 14q chromosome, plays a crucial role in the advancement of GISTs. […] Multiple genomic events targeting cell-related genes, including RB1 and TP53 mutation/copy loss, have been linked to GIST progression. […] Furthermore, Niinuma et al revealed that MEG3, located on chromosome 14q, is involved in the pathogenesis of GISTs and is associated with poor prognosis in patients with GISTs. […] The advent of targeted therapy has revolutionized the prognosis of patients with advanced GISTs; however, the emergence of drug resistance remains a significant challenge that warrants further investigation.

• #50 Molecular Mechanisms of Gastrointestinal Stromal – ProQuest

  https://www.proquest.com/scholarly-journals/molecular-mechanisms-gastrointestinal-stromal/docview/2785176701/se-2

  Improved understanding of the molecular biology of the disease and the identification of driver alterations and mechanisms of resistance to systemic therapies have resulted in advances in the systemic treatment of GISTs, thereby broadening the systemic therapy armamentarium. […] Tyrosine kinase inhibitors (TKIs) represent the standard systemic therapy and comprise various targeted drugs. […] Despite the convincing achievements with TKI treatment, targeted therapy eventually leads to the development of drug resistance. Secondary mutations play a major role in this process, allowing for the selection of cells that are resistant to the treatment applied. […] The proto-oncogene KIT encodes the KIT receptor, which is a type III receptor tyrosine kinase (RTK); it belongs to a family of RTKs that also includes PDGFRA.

• #51 Molecular Mechanisms of Gastrointestinal Stromal – ProQuest

  https://www.proquest.com/scholarly-journals/molecular-mechanisms-gastrointestinal-stromal/docview/2785176701/se-2

  However, there is a group of patients who respond worse to imatinib initiation; namely, some patients with KIT exon 11 mutations who, at the same time, bear polymorphisms in genes involved in imatinib metabolism. […] Disease progression is frequently due to the occurrence of secondary mutations resulting from evolutionary selection pressure during imatinib treatment. […] Secondary mutations occur mainly at specific sites in KIT or PDGFRA. […] The mechanisms of secondary mutations in PDGFRA are poorly understood, with well-known primary resistance to imatinib only in PDGFRA D482V. […] Other mechanisms of GIST resistance to imatinib are infrequent and poorly understood. […] Gastrointestinal stromal tumors with a deficient SDH complex do not respond to imatinib treatment but, in line with the mechanism of oncogenesis, they respond to multitargeted TKIs. […] Gastrointestinal stromal tumors with NTRK rearrangements do not respond to treatment with imatinib or sunitinib but do respond to treatment with NTRK inhibitors.

• #52 Ripretinib in the treatment of patients with advanced gastrointestinal stromal tumors (GIST) | Babula | Oncology in Clinical Practice

  https://journals.viamedica.pl/oncology_in_clinical_practice/article/view/96771

  Disease progression during treatment with kinase inhibitors is most often due to new secondary mutations in KIT or PDGFRA, which are located mainly in the KIT ATP binding domain (exons 13 and 14) or the activation loop (exons 17 and 18) and, in the case of PDGFRA, in the ATP binding domain (exons 13, 14, 15). […] Ripretinib is a new inhibitor of tyrosine kinases, particularly KIT kinase, which has found its application in treating unresectable and resistant forms of GISTs. […] Ripretinib, as the first of the KIT inhibitors, is applicable in inhibiting all tested KIT and PDGFRA mutations, except for the D842V mutation, but also in wild-type GISTs. […] Its innovative mechanism of action is based on the inhibition of two domains related to exon 11 and exon 9, regardless of the type of mutation, primary or secondary. […] Ripretinib has a dual-pronged effect. It is an antagonist because it blocks the phosphorylation of the switch and the activation loop, preventing the transformation of KIT into the active form. At the same time, it plays a stabilizing role.

• #53 Ripretinib in the treatment of patients with advanced gastrointestinal stromal tumors (GIST) | Babula | Oncology in Clinical Practice

  https://journals.viamedica.pl/oncology_in_clinical_practice/article/view/96771

  Disease progression during treatment with kinase inhibitors is most often due to new secondary mutations in KIT or PDGFRA, which are located mainly in the KIT ATP binding domain (exons 13 and 14) or the activation loop (exons 17 and 18) and, in the case of PDGFRA, in the ATP binding domain (exons 13, 14, 15). […] Ripretinib is a new inhibitor of tyrosine kinases, particularly KIT kinase, which has found its application in treating unresectable and resistant forms of GISTs. […] Ripretinib, as the first of the KIT inhibitors, is applicable in inhibiting all tested KIT and PDGFRA mutations, except for the D842V mutation, but also in wild-type GISTs. […] Its innovative mechanism of action is based on the inhibition of two domains related to exon 11 and exon 9, regardless of the type of mutation, primary or secondary. […] Ripretinib has a dual-pronged effect. It is an antagonist because it blocks the phosphorylation of the switch and the activation loop, preventing the transformation of KIT into the active form. At the same time, it plays a stabilizing role.

• #54

  https://xiahepublishing.com/2310-8819/JCTH-2022-00173

  Tumor genotypes are important to determine and need to be correlated with molecular types and drug therapy to increase understanding of pathways for successful treatment and to provide more insight concerning resistance. […] PDGFRA mutations 18, 12, and 14 have been reported to be associated with resistance to imatinib, sunitinib, and regorafenib, listed from high to low frequency, respectively. […] Other treatments can be used in combination, such as resection, transarterial therapies, and tumor ablation.

• #55 The Important Role of PDGFRA in the Pathogenesis of Gastrointestinal Stromal Tumors (GISTs)

  https://www.linkedin.com/pulse/important-role-pdgfra-pathogenesis-gastrointestinal-stromal

  Gastrointestinal Stromal Tumors (GISTs) are gastrointestinal mesenchymal tumors that commonly originate from the digestive tract. The activation mutations of the KIT or PDGFRA genes are the main drivers of GIST development. The most common mutations in GISTs are those of the KIT gene and PDGFRA gene. The platelet-derived growth factor receptor alpha (PDGFRA) gene encodes a receptor tyrosine kinase that binds to its corresponding ligands and plays a crucial regulatory role in embryonic development, cell proliferation, survival, and chemotaxis processes. […] Most primary and secondary resistance mutations in PDGFRA are located within the conformation control switch region of the intracellular kinase domain. Primary mutations are frequently found in the activation loop, while secondary mutations typically occur in the ATP-binding domain (exon 14) or activation loop (exon 18). Mutations in PDGFRA are mainly observed in exons 18 and 12, and rarely in exon 14. Mutations in exon 18, which encodes the D842V site, account for approximately 80% of PDGFRA mutations in GISTs. Studies have found that the D842V mutation in the PDGFRA gene is responsible for primary resistance to imatinib in GIST patients. PDGFRA mutations are independent of C-KIT gene mutations. Therefore, testing for PDGFRA gene mutations in tumor patients can be used to determine the efficacy of imatinib treatment. […] The PDGFR signaling pathway is an important receptor tyrosine kinase pathway that is involved in the physiological activities of various tumors. Inhibiting PDGFR can reduce cancer proliferation, metastasis, invasion, and angiogenesis, and improve the anti-tumor effects of anticancer drugs.

• #56 Ripretinib in the treatment of patients with advanced gastrointestinal stromal tumors (GIST) | Babula | Oncology in Clinical Practice

  https://journals.viamedica.pl/oncology_in_clinical_practice/article/view/96771

  Disease progression during treatment with kinase inhibitors is most often due to new secondary mutations in KIT or PDGFRA, which are located mainly in the KIT ATP binding domain (exons 13 and 14) or the activation loop (exons 17 and 18) and, in the case of PDGFRA, in the ATP binding domain (exons 13, 14, 15). […] Ripretinib is a new inhibitor of tyrosine kinases, particularly KIT kinase, which has found its application in treating unresectable and resistant forms of GISTs. […] Ripretinib, as the first of the KIT inhibitors, is applicable in inhibiting all tested KIT and PDGFRA mutations, except for the D842V mutation, but also in wild-type GISTs. […] Its innovative mechanism of action is based on the inhibition of two domains related to exon 11 and exon 9, regardless of the type of mutation, primary or secondary. […] Ripretinib has a dual-pronged effect. It is an antagonist because it blocks the phosphorylation of the switch and the activation loop, preventing the transformation of KIT into the active form. At the same time, it plays a stabilizing role.

• #57 Gastrointestinal Stromal Tumors Treatment (PDQ®) – NCI

  https://www.cancer.gov/types/soft-tissue-sarcoma/hp/gist-treatment-pdq

  Gastrointestinal stromal tumors (GISTs) appear to originate from interstitial cells of Cajal (ICC) or their stem cell-like precursors. ICC are pacemaker-like intermediates between the gastrointestinal (GI) autonomic nervous system and smooth muscle cells regulating GI motility and autonomic nerve function. ICC are located around the myenteric plexus and the muscularis propria throughout the GI tract. ICC or their stem cell-like precursors can differentiate into smooth muscle cells if KIT signaling is disrupted. […] Approximately 85% of GISTs contain oncogenic variants in one of two receptor tyrosine kinases (RTKs): KIT and PDGFRA. Constitutive activation of either of these RTKs plays a central role in the pathogenesis of GISTs. […] Tumors without detectable KIT or PDGFRA variants account for 12% to 15% of all GISTs. Less than 5% of GISTs occur in patients with syndromic diseases, such as neurofibromatosis type 1 (NF1), Carney triad syndrome (SDH deletion), and other familial diseases.

• #58 Molecular Mechanisms of Gastrointestinal Stromal – ProQuest

  https://www.proquest.com/scholarly-journals/molecular-mechanisms-gastrointestinal-stromal/docview/2785176701/se-2

  Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract, but they account for less than 1% of all gastrointestinal tumors. […] Gastrointestinal stromal tumors generally arise from pacemaker (Cajal) cells anywhere in the digestive tube from the esophagus to the rectum but, more recently, evidence has shown that they can also arise from telocytes or smooth muscle cells. […] They are a heterogeneous group of diseases of different molecular subtypes, with oncogenesis mainly resulting from mutually exclusive activating mutations, most commonly in the KIT proto-oncogene (KIT) or the platelet-derived growth factor receptor alpha gene (PDGFRA). […] Around 5% of GISTs are syndromic and associated with germline mutations in genes encoding for KIT, PDGFRA, succinate dehydrogenase B/C/D (SDHB/C/D) (Carney Stratakis syndrome), and neurofibromin or with epigenetic silencing of SDHC (nonhereditary Carney triad syndrome).

• #59 Gastrointestinal Stromal Tumors (GISTs): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/278845-overview

  A small minority of GISTs are associated with hereditary syndromes. […] Familial GISTs are characterized by inherited germline mutations in KIT or PDGFRA and additional findings such as cutaneous hyperpigmentation, irritable bowel syndrome, dysphagia, and diverticular disease. […] Of individuals with these germline mutations, 90% may develop GISTs by 70 years of age.

• #60 Gastrointestinal Stromal Tumors (GISTs): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/278845-overview

  A small minority of GISTs are associated with hereditary syndromes. […] Familial GISTs are characterized by inherited germline mutations in KIT or PDGFRA and additional findings such as cutaneous hyperpigmentation, irritable bowel syndrome, dysphagia, and diverticular disease. […] Of individuals with these germline mutations, 90% may develop GISTs by 70 years of age.

• #61 Molecular characterization and pathogenesis of gastrointestinal stromal tumor

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5803009/

  Mutations in RAS family genes and BRAF are found in a subset of GISTs. […] The BRAF V600E mutation is detected in malignant melanoma and thyroid and colorectal cancers. […] The mutant BRAF cooperates with Rac1b, AKT3 and other signal molecules to promote tumor cell viability and proliferation. […] Neurofibromatosis type1 is an inheritable disease caused by bi-allelic loss of the NF1 gene. […] Individuals with NF1 mutations are at high risk of developing GISTs. […] Chromosomal aberrations are prevalent among GISTs, with approximately 60% to 70% of all GISTs exhibiting alterations in chromosome 14, including loss of 14q and monosomy 14. […] In addition, nearly half of GISTs show loss of 22q, while losses of 1p, 9p, 10q, 11p, 13q, 15q and 17p are also reported with lesser frequencies.

• #62 Molecular characterization and pathogenesis of gastrointestinal stromal tumor – Niinuma – Translational Gastroenterology and Hepatology

  https://tgh.amegroups.org/article/view/4057/html

  Inhibition of IGF1R induces apoptosis and represses AKT and MAPK signaling in GIST cells, which implicates the IGF signal in the development of SDH-deficient GISTs. […] Neurofibromatosis type1 is an inheritable disease caused by bi-allelic loss of the NF1 gene. […] NF1-associated GISTs do not harbor KIT/PDGFRA mutations; instead, loss of NF1 leads to MAPK signal activation, while PI3K-AKT and JAK-STAT signals are less active than in common GISTs. […] Chromosomal aberrations are prevalent among GISTs, with approximately 60% to 70% of all GISTs exhibiting alterations in chromosome 14, including loss of 14q and monosomy 14. […] In addition, nearly half of GISTs show loss of 22q, while losses of 1p, 9p, 10q, 11p, 13q, 15q and 17p are also reported with lesser frequencies. […] A number of functionally important genes are located in the regions frequently deleted in GISTs, including PARP2, APEX1, and NDRG2 at 14q11.2; SIVA at 14q32.33; MAX at 14q23.3; and NF2 at 22q12.2. […] SETD2 mutations were recently identified in high-risk and metastatic GISTs. […] Loss of SETD2 is associated with reduced H3K36me3, DNA hypomethylated heterochromatin, and significantly worse outcomes in GIST patients, which suggests SETD2 is a novel GIST tumor suppressor.

• #63 GIST (Gastrointestinal Stromal Tumor) | Memorial Sloan Kettering Cancer Center

  https://www.mskcc.org/cancer-care/types/soft-tissue-sarcoma/types/gist-gastrointestinal-stromal-tumor

  A gastrointestinal stromal tumor (GIST) is a rare cancer. It is a type of soft tissue sarcoma that often begins in the abdomen. […] No one knows exactly what causes GISTs. These tumors commonly have genetic abnormalities in the KIT gene or other similar genes. Some people have a higher risk for a GIST due to inherited genetic mutations. Inherited GIST makes it more likely for someone to develop multiple tumors in the stomach or the part of the small intestine called the jejunum. GISTs that run in families are closely associated with KIT mutations. […] People with type I neurofibromatosis are also more likely to develop a GIST.

• #64 Syndromic gastrointestinal stromal tumors | Hereditary Cancer in Clinical Practice | Full Text

  https://hccpjournal.biomedcentral.com/articles/10.1186/s13053-016-0055-4

  The oncological impact of individual syndromic KIT-mutant GISTs is estimated using the parameters adopted for their sporadic counterparts. […] NF1 inactivation stimulates MAPK cascade through increasing RAS activity, promoting tumorigenesis. […] NF1-associated GISTs are often multiple and small intestinal, with possible gastric exceptions; singly considered, they do not differ from sporadic intestinal GISTs, mostly featuring spindle cells, collagen globules (skeinoid fibers) and CD117 positivity. […] The discovery of NF1 second-hit in NF1 GISTs disclosed their pathogenesis and molecular link with NF1. […] NF1 GIST tumoral progression resembles that of germline KIT mutants, featuring preneoplastic ICCH followed by 14q and 22q LOH. […] SDH deficiency is also a feature of paragangliomas, renal cell carcinomas and pituitary adenomas. SDH-deficient GISTs arise either in germline SDHx-mutant and/or manifest syndromic settings or not.

• #65 Molecular characterization and pathogenesis of gastrointestinal stromal tumor – Niinuma – Translational Gastroenterology and Hepatology

  https://tgh.amegroups.org/article/view/4057/html

  Inhibition of IGF1R induces apoptosis and represses AKT and MAPK signaling in GIST cells, which implicates the IGF signal in the development of SDH-deficient GISTs. […] Neurofibromatosis type1 is an inheritable disease caused by bi-allelic loss of the NF1 gene. […] NF1-associated GISTs do not harbor KIT/PDGFRA mutations; instead, loss of NF1 leads to MAPK signal activation, while PI3K-AKT and JAK-STAT signals are less active than in common GISTs. […] Chromosomal aberrations are prevalent among GISTs, with approximately 60% to 70% of all GISTs exhibiting alterations in chromosome 14, including loss of 14q and monosomy 14. […] In addition, nearly half of GISTs show loss of 22q, while losses of 1p, 9p, 10q, 11p, 13q, 15q and 17p are also reported with lesser frequencies. […] A number of functionally important genes are located in the regions frequently deleted in GISTs, including PARP2, APEX1, and NDRG2 at 14q11.2; SIVA at 14q32.33; MAX at 14q23.3; and NF2 at 22q12.2. […] SETD2 mutations were recently identified in high-risk and metastatic GISTs. […] Loss of SETD2 is associated with reduced H3K36me3, DNA hypomethylated heterochromatin, and significantly worse outcomes in GIST patients, which suggests SETD2 is a novel GIST tumor suppressor.

• #66 Pathology Outlines – Gastrointestinal stromal tumor (GIST)

  https://www.pathologyoutlines.com/topic/softtissueGIST.html

  Therapeutic strategy to treat GISTs with either KIT or PDGFRA mutations has been the use of TKIs, especially imatinib. […] Since most NF1 mutant GISTs do not harbor KIT mutations, they are typically insensitive to imatinib and surgery remains the mainstay therapy for these patients. […] This subtype of GIST is known to be generally unresponsive to TKIs.

• #67 Molecular Mechanisms of Gastrointestinal Stromal – ProQuest

  https://www.proquest.com/scholarly-journals/molecular-mechanisms-gastrointestinal-stromal/docview/2785176701/se-2

  Molecular analysis is an important factor influencing decision about systemic treatment for both limited and metastatic disease. […] The two methods so far predominantly used to identify molecular markers are reverse transcription polymerase chain reaction (RT-PCR) and direct Sanger sequencing. […] For these reasons, NGS, which has a substantially lower detection limit and allows for the identification of changes in a large number of genes in several samples simultaneously, is progressively entering routine diagnostics. […] The European Society of Medical Oncology (ESMO) guidelines for the management of patients with GISTs recommend centralization of molecular testing, although they allow either Sanger sequencing or NGS as the applied method. […] The goal of systemic treatment of metastatic or unresectable KIT/PDGFRA-mutated GISTs with imatinib is to prolong survival with good quality of life.

• #68 Molecular Mechanisms of Gastrointestinal Stromal – ProQuest

  https://www.proquest.com/scholarly-journals/molecular-mechanisms-gastrointestinal-stromal/docview/2785176701/se-2

  Molecular analysis is an important factor influencing decision about systemic treatment for both limited and metastatic disease. […] The two methods so far predominantly used to identify molecular markers are reverse transcription polymerase chain reaction (RT-PCR) and direct Sanger sequencing. […] For these reasons, NGS, which has a substantially lower detection limit and allows for the identification of changes in a large number of genes in several samples simultaneously, is progressively entering routine diagnostics. […] The European Society of Medical Oncology (ESMO) guidelines for the management of patients with GISTs recommend centralization of molecular testing, although they allow either Sanger sequencing or NGS as the applied method. […] The goal of systemic treatment of metastatic or unresectable KIT/PDGFRA-mutated GISTs with imatinib is to prolong survival with good quality of life.

• #69 Gastrointestinal stromal tumor – Zhao – Journal of Gastrointestinal Oncology

  https://jgo.amegroups.org/article/view/434/html

  Furthermore, GISTs demonstrate typical patterns of chromosomal gains and losses, including losses at 1p, 14q, 15q, and 22q. […] KIT oncogenetic activation is the dominant pathogenetic mechanism in GIST. […] The most common mutations in KIT are found in the juxtamembrane domain that is encoded by the 5′ end of exon 11 of the KIT receptor. […] The mutations vary from in-frame deletions of variable sizes, point mutations to deletions preceded by substitutions. […] The deletions are associated with a more aggressive behavior in comparison to other exon 11 mutations. […] A less common mutant spot is located at the 3′ end of exon 11, which includes mainly internal tandem duplications mutations. […] The second most common KIT mutation, between 10% and 15% of GISTs, is a mutation in an extracellular domain encoded by exon 9.

• #70 Molecular Mechanisms of Gastrointestinal Stromal – ProQuest

  https://www.proquest.com/scholarly-journals/molecular-mechanisms-gastrointestinal-stromal/docview/2785176701/se-2

  Molecular analysis is an important factor influencing decision about systemic treatment for both limited and metastatic disease. […] The two methods so far predominantly used to identify molecular markers are reverse transcription polymerase chain reaction (RT-PCR) and direct Sanger sequencing. […] For these reasons, NGS, which has a substantially lower detection limit and allows for the identification of changes in a large number of genes in several samples simultaneously, is progressively entering routine diagnostics. […] The European Society of Medical Oncology (ESMO) guidelines for the management of patients with GISTs recommend centralization of molecular testing, although they allow either Sanger sequencing or NGS as the applied method. […] The goal of systemic treatment of metastatic or unresectable KIT/PDGFRA-mutated GISTs with imatinib is to prolong survival with good quality of life.

• #71 Syndromic gastrointestinal stromal tumors | Hereditary Cancer in Clinical Practice | Full Text

  https://hccpjournal.biomedcentral.com/articles/10.1186/s13053-016-0055-4

  SDH-deficient GISTs often behave indolently, even in case of metastases, probably due to the metabolic disadvantage caused by SDH deficiency. […] TKI imatinib and sunitinib proved ineffective or only partially effective, respectively, in SDH-deficient GISTs, coherently with SHD deficiency constituting a pathway independent of KIT/PDGFRA.

• #72 Molecular Mechanisms of Gastrointestinal Stromal – ProQuest

  https://www.proquest.com/scholarly-journals/molecular-mechanisms-gastrointestinal-stromal/docview/2785176701/se-2

  Molecular analysis is an important factor influencing decision about systemic treatment for both limited and metastatic disease. […] The two methods so far predominantly used to identify molecular markers are reverse transcription polymerase chain reaction (RT-PCR) and direct Sanger sequencing. […] For these reasons, NGS, which has a substantially lower detection limit and allows for the identification of changes in a large number of genes in several samples simultaneously, is progressively entering routine diagnostics. […] The European Society of Medical Oncology (ESMO) guidelines for the management of patients with GISTs recommend centralization of molecular testing, although they allow either Sanger sequencing or NGS as the applied method. […] The goal of systemic treatment of metastatic or unresectable KIT/PDGFRA-mutated GISTs with imatinib is to prolong survival with good quality of life.

• #73 Molecular characterization and pathogenesis of gastrointestinal stromal tumor – Niinuma – Translational Gastroenterology and Hepatology

  https://tgh.amegroups.org/article/view/4057/html

  Most gastrointestinal stromal tumors (GISTs) harbor activating mutations in the receptor tyrosine kinase gene KIT or platelet-derived growth factor receptor alpha (PDGFRA), and the resultant activation of downstream signals plays a pivotal role in the development of GISTs. […] Activating mutations in the receptor tyrosine kinase gene KIT or platelet-derived growth factor receptor alpha (PDGFRA) play essential roles in the pathogenesis of GISTs through upregulation of downstream signaling pathways, including RAS/RAF/MAPK and PI3K/AKT/mTOR. […] Neurofibromin 1 (NF1) also acts as a tumor suppressor gene in GISTs, and patients with neurofibromatosis type I are known to be at high risk of developing multiple GISTs. […] SDH deficiency and the resultant accumulation of succinate promote GIST development through different mechanisms than do oncogenic mutations, including upregulation of HIF1 and inhibition of DNA demethylation.

• #74 Gastrointestinal Stromal Tumors (GISTs): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/278845-overview

  Gastrointestinal stromal tumors (GISTs) account for less than 1% of GI tumors, but they are the most common mesenchymal neoplasms of the GI tract. […] According to the work of Kindblom and associates, reported in 1998, the actual cell of origin of GISTs is a pluripotential mesenchymal stem cell programmed to differentiate into the interstitial cell of Cajal. […] Additional studies found that interstitial cells of Cajal express KIT and are developmentally dependent on stem cell factor, which is regulated through KIT kinase. […] Perhaps the most critical development that distinguished GISTs as a unique clinical entity was the discovery of c-KIT proto-oncogene mutations in these tumors in by Hirota and colleagues in 1998. […] Activating KIT mutations are seen in 85-95% of GISTs. […] The PDGFR alpha mutation seems to leave the PDGFRalpha receptor constitutively active and may represent an alternate pathway with activation of similar downstream signaling as the KIT receptor.

• #75 Understanding Gastric GIST: From Pathophysiology to Personalized Treatment

  https://www.mdpi.com/2077-0383/13/14/3997

  Gastric gastrointestinal stromal tumors (GISTs) represent a subset of gastrointestinal tumors predominantly found in the stomach. Despite their rarity, these tumors carry significant implications for patient health and management. GISTs are potentially malignant tumors with unpredictable progression. They originate from the interstitial cells of Cajal, which are positioned between the intramural neurons and the smooth muscle cells of the digestive tract. These tumors are characterized primarily by mutations in the c-Kit gene, as well as other mutations such as those in the platelet-derived growth factor receptor alpha (PDGFRA) gene. […] The hallmark of gastric GIST pathophysiology lies in the dysregulation of receptor tyrosine kinase (RTK) signaling pathways, primarily involving the KIT (CD117) and platelet-derived growth factor receptor alpha (PDGFRA) genes. These mutations lead to constitutive activation of downstream signaling cascades, including the RAS-RAF-MEK-ERK and PI3K-AKT-mTOR pathways, resulting in uncontrolled cellular proliferation and inhibition of apoptosis. In gastric GISTs, aberrant activation of KIT and PDGFRA promotes tumor growth and progression by stimulating cell cycle progression, enhancing angiogenesis, and facilitating evasion of immune surveillance mechanisms. Additionally, dysregulated signaling within the tumor microenvironment promotes tumor invasion and metastasis, contributing to the aggressive behavior observed in some cases.

• #76 Update on Molecular Genetics of Gastrointestinal Stromal Tumors

  https://www.mdpi.com/2075-4418/11/2/194

  It is well known that approximately 80% of GISTs harbor activating mutations in the KIT or PDGFRA genes that are responsible for the up-regulation of crucial signaling pathways including MAPK and PI3K-AKT. On the other hand, GISTs lacking KIT and PDGFRA mutations are referred to as “wild-type” (wt)-GISTs. These tumors differ from KIT and PDGFRA-mutant GISTs with regard to their clinical behavior and heterogenetic molecular profile. Over the past few years, advances in molecular pathology helped to elucidate alternative molecular drivers in the non KIT- non PDGFRA- mutated so-called “wt”-GIST group. Alternative mutations, structural chromosomal and epigenetic changes have been demonstrated in this group making the molecular classification more complex. Recent insights about the crucial role of the SDH-complex, especially in the pathobiology of pediatric GISTs, helped to divide GISTs by immunohistochemistry in a succinate dehydrogenase B (SDHB)-retained and SDHB-deficient subgroup. This widely available screening approach can facilitate decisions on further molecular testing strategies.

• #77 Molecular characterization and pathogenesis of gastrointestinal stromal tumor – Niinuma – Translational Gastroenterology and Hepatology

  https://tgh.amegroups.org/article/view/4057/html

  Recent studies have shown that epigenetic alterations and noncoding RNAs also play key roles in the pathogenesis of GISTs. […] GISTs with no mutations in KIT, PDGFRA or RAS pathway genes or SDH-deficiency are referred as wild-type GISTs. […] A subset of wild-type GISTs exhibit mutations in TP53, MEN1 or MAX, and are characterized by a neural-committed phenotype and upregulation of the master endocrine regulator ASCL1. […] Epigenetic alterations, including aberrant DNA methylation and histone modification, have also been implicated in the development of GISTs. […] Accumulation of succinate is also involved in the stabilization of HIF1-, which controls oncogene transcription. […] The IGF family consists of two ligands (IGF1 and IGF2), two receptors (IGFR1 and IGFR1) and 6 IGF binding proteins (IGFBPs), and binding of IGF and IGFR activates downstream signals, including the MAPK and PI3K/AKT pathways.

• #78 Molecular characterization and pathogenesis of gastrointestinal stromal tumor – Niinuma – Translational Gastroenterology and Hepatology

  https://tgh.amegroups.org/article/view/4057/html

  Inhibition of IGF1R induces apoptosis and represses AKT and MAPK signaling in GIST cells, which implicates the IGF signal in the development of SDH-deficient GISTs. […] Neurofibromatosis type1 is an inheritable disease caused by bi-allelic loss of the NF1 gene. […] NF1-associated GISTs do not harbor KIT/PDGFRA mutations; instead, loss of NF1 leads to MAPK signal activation, while PI3K-AKT and JAK-STAT signals are less active than in common GISTs. […] Chromosomal aberrations are prevalent among GISTs, with approximately 60% to 70% of all GISTs exhibiting alterations in chromosome 14, including loss of 14q and monosomy 14. […] In addition, nearly half of GISTs show loss of 22q, while losses of 1p, 9p, 10q, 11p, 13q, 15q and 17p are also reported with lesser frequencies. […] A number of functionally important genes are located in the regions frequently deleted in GISTs, including PARP2, APEX1, and NDRG2 at 14q11.2; SIVA at 14q32.33; MAX at 14q23.3; and NF2 at 22q12.2. […] SETD2 mutations were recently identified in high-risk and metastatic GISTs. […] Loss of SETD2 is associated with reduced H3K36me3, DNA hypomethylated heterochromatin, and significantly worse outcomes in GIST patients, which suggests SETD2 is a novel GIST tumor suppressor.

• #79 Molecular Mechanisms of Gastrointestinal Stromal – ProQuest

  https://www.proquest.com/scholarly-journals/molecular-mechanisms-gastrointestinal-stromal/docview/2785176701/se-2

  However, there is a group of patients who respond worse to imatinib initiation; namely, some patients with KIT exon 11 mutations who, at the same time, bear polymorphisms in genes involved in imatinib metabolism. […] Disease progression is frequently due to the occurrence of secondary mutations resulting from evolutionary selection pressure during imatinib treatment. […] Secondary mutations occur mainly at specific sites in KIT or PDGFRA. […] The mechanisms of secondary mutations in PDGFRA are poorly understood, with well-known primary resistance to imatinib only in PDGFRA D482V. […] Other mechanisms of GIST resistance to imatinib are infrequent and poorly understood. […] Gastrointestinal stromal tumors with a deficient SDH complex do not respond to imatinib treatment but, in line with the mechanism of oncogenesis, they respond to multitargeted TKIs. […] Gastrointestinal stromal tumors with NTRK rearrangements do not respond to treatment with imatinib or sunitinib but do respond to treatment with NTRK inhibitors.

• #80 Molecular Mechanisms of Gastrointestinal Stromal – ProQuest

  https://www.proquest.com/scholarly-journals/molecular-mechanisms-gastrointestinal-stromal/docview/2785176701/se-2

  Improved understanding of the molecular biology of the disease and the identification of driver alterations and mechanisms of resistance to systemic therapies have resulted in advances in the systemic treatment of GISTs, thereby broadening the systemic therapy armamentarium. […] Tyrosine kinase inhibitors (TKIs) represent the standard systemic therapy and comprise various targeted drugs. […] Despite the convincing achievements with TKI treatment, targeted therapy eventually leads to the development of drug resistance. Secondary mutations play a major role in this process, allowing for the selection of cells that are resistant to the treatment applied. […] The proto-oncogene KIT encodes the KIT receptor, which is a type III receptor tyrosine kinase (RTK); it belongs to a family of RTKs that also includes PDGFRA.

• #81

  https://journals.lww.com/otm/fulltext/2024/06000/systemic_therapy_in_gastrointestinal_stromal.3.aspx

  The MYC-associated factor X (MAX) gene, located on the 14q chromosome, plays a crucial role in the advancement of GISTs. […] Multiple genomic events targeting cell-related genes, including RB1 and TP53 mutation/copy loss, have been linked to GIST progression. […] Furthermore, Niinuma et al revealed that MEG3, located on chromosome 14q, is involved in the pathogenesis of GISTs and is associated with poor prognosis in patients with GISTs. […] The advent of targeted therapy has revolutionized the prognosis of patients with advanced GISTs; however, the emergence of drug resistance remains a significant challenge that warrants further investigation.

• #82 Molecular Mechanisms of Gastrointestinal Stromal – ProQuest

  https://www.proquest.com/scholarly-journals/molecular-mechanisms-gastrointestinal-stromal/docview/2785176701/se-2

  However, there is a group of patients who respond worse to imatinib initiation; namely, some patients with KIT exon 11 mutations who, at the same time, bear polymorphisms in genes involved in imatinib metabolism. […] Disease progression is frequently due to the occurrence of secondary mutations resulting from evolutionary selection pressure during imatinib treatment. […] Secondary mutations occur mainly at specific sites in KIT or PDGFRA. […] The mechanisms of secondary mutations in PDGFRA are poorly understood, with well-known primary resistance to imatinib only in PDGFRA D482V. […] Other mechanisms of GIST resistance to imatinib are infrequent and poorly understood. […] Gastrointestinal stromal tumors with a deficient SDH complex do not respond to imatinib treatment but, in line with the mechanism of oncogenesis, they respond to multitargeted TKIs. […] Gastrointestinal stromal tumors with NTRK rearrangements do not respond to treatment with imatinib or sunitinib but do respond to treatment with NTRK inhibitors.

• #83 Molecular Mechanisms of Gastrointestinal Stromal – ProQuest

  https://www.proquest.com/scholarly-journals/molecular-mechanisms-gastrointestinal-stromal/docview/2785176701/se-2

  With advances in molecular diagnostic techniques, in particular, with the use of next-generation sequencing (NGS) technology, the mechanisms of oncogenesis can be more precisely defined, even in historical WT GISTs. […] Taking this fact into account, KIT/PDGFRA mutations represent the driving mutations in as many as 92-93% of all GISTs. […] In 57.5% of all GISTs, the driving oncogene mechanism is related to a deficiency in the succinate dehydrogenase (SDH) complex. […] When no KIT/PDGFRA mutations are detected and the SDH complex is competent, various very rare driver alterations have been identified. […] Different molecular mechanisms in GISTs lead to different clinical courses of the disease and, in particular, different responses to systemic imatinib treatment. […] Therefore, it is necessary to identify the driving alterations before initiating the first systemic therapy, both in (neo)adjuvant settings and as the first systemic therapy for metastatic disease.

• #84

  https://xiahepublishing.com/2310-8819/JCTH-2022-00173

  Tumor genotypes are important to determine and need to be correlated with molecular types and drug therapy to increase understanding of pathways for successful treatment and to provide more insight concerning resistance. […] PDGFRA mutations 18, 12, and 14 have been reported to be associated with resistance to imatinib, sunitinib, and regorafenib, listed from high to low frequency, respectively. […] Other treatments can be used in combination, such as resection, transarterial therapies, and tumor ablation.

• #85

  https://www.omim.org/entry/606764

  Janeway et al. (2011) evaluated SDHB (185470) expression in 30 GISTs lacking KIT or PDGFRA (173490) mutations, 25 of which were also negative for associated SDH mutations confirmed by sequence analysis. Immunohistochemical studies showed lack of SDHB staining in 18 (100%) of 18 pediatric tumors, regardless of SDH mutation status, and in 8 (67%) of 12 adult tumors and weak expression in 4 (33%) of 12 adult tumors. By comparison, only 1 of 18 KIT-mutant GISTs and 0 of 5 NF1-associated GISTs lacked SDHB expression. These findings implicated a defect in respiration in the pathogenesis of some GIST tumors. […] A subset of gastrointestinal stromal tumors (GISTs) lack canonical kinase mutations but instead have SDH deficiency and global DNA hypermethylation. Flavahan et al. (2019) associated this hypermethylation with changes in genome topology that activate oncogenic programs. To investigate epigenetic alterations systematically, Flavahan et al. (2019) mapped DNA methylation, CTCF (604167) insulators, enhancers, and chromosome topology in KIT-mutant, PDGFRA-mutant, and SDH-deficient GISTs. Although these respective subtypes shared similar enhancer landscapes, Flavahan et al. (2019) identified hundreds of putative insulators where DNA methylation replaced CTCF binding in SDH-deficient GISTs. Flavahan et al. (2019) focused on a disrupted insulator that normally partitions a core GIST superenhancer from the FGF4 (164980) oncogene. Recurrent loss of this insulator alters locus topology in SDH-deficient GISTs, allowing aberrant physical interaction between enhancer and oncogene. CRISPR-mediated excision of the corresponding CTCF motifs in an SDH-intact GIST model disrupted the boundary between enhancer and oncogene, and strongly upregulated FGF4 expression. Flavahan et al. (2019) also identified a second recurrent insulator loss event near the KIT oncogene, which is also highly expressed across SDH-deficient GISTs. The authors established a patient-derived xenograft from an SDH-deficient GIST that faithfully maintained the epigenetics of the parental tumor, including hypermethylation and insulator defects. This patient-derived xenograft model was highly sensitive to FGF receptor inhibition, and more so to combined FGFR and KIT inhibition, validating the functional significance of the underlying epigenetic lesions.

• #86 Molecular Mechanisms of Gastrointestinal Stromal – ProQuest

  https://www.proquest.com/scholarly-journals/molecular-mechanisms-gastrointestinal-stromal/docview/2785176701/se-2

  With advances in molecular diagnostic techniques, in particular, with the use of next-generation sequencing (NGS) technology, the mechanisms of oncogenesis can be more precisely defined, even in historical WT GISTs. […] Taking this fact into account, KIT/PDGFRA mutations represent the driving mutations in as many as 92-93% of all GISTs. […] In 57.5% of all GISTs, the driving oncogene mechanism is related to a deficiency in the succinate dehydrogenase (SDH) complex. […] When no KIT/PDGFRA mutations are detected and the SDH complex is competent, various very rare driver alterations have been identified. […] Different molecular mechanisms in GISTs lead to different clinical courses of the disease and, in particular, different responses to systemic imatinib treatment. […] Therefore, it is necessary to identify the driving alterations before initiating the first systemic therapy, both in (neo)adjuvant settings and as the first systemic therapy for metastatic disease.

• #87 Gastrointestinal stromal tumors (GISTs): What are they, and how are they treated? | MD Anderson Cancer Center

  https://www.mdanderson.org/cancerwise/gastrointestinal-stromal-tumors–gists—what-are-they-and-how-are-they-treated.h00-159699123.html

  Gastrointestinal stromal tumors form when interstitial cells of Cajal grow abnormally and turn into cancer. […] Most GISTs arise because of a random mutation in a cells KIT or PDGFR gene that occurs sporadically, meaning theres no known cause. […] The type of mutation and location of the mutation in the KIT or PDGFR gene determines how well the GIST will respond to the drug. […] Often, GISTs that respond to imatinib might eventually stop responding. This resistance to imatinib occurs because the GIST can develop secondary mutations. […] GISTs can be cured if theyre caught early and can be removed by surgery. […] Its more challenging to treat large, bulky tumors that are getting bigger on imatinib because subsequent therapies may not offer long-lasting benefits. This is often due to the presence of new secondary mutations. […] Catching GISTs early and treating them based on the mutation type can improve your chances of survival.

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