BRAF mutations in KIT/PDGFRA positive gastrointestinal stromal tumours (GISTs): Is their frequency underestimated?

Jašek, Karin; Váňová, Barbora; Grendár, Marian; Stanclova, Andrea; Szépe, P; Horňáková, Andrea; Holubeková, Veronika; Lasabová, Zora

doi:10.1016/j.prp.2020.153171

Cited by 10 publications

(7 citation statements)

References 28 publications

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“…The gene mutation is obviously related to familial gastrointestinal stromal tumors and other cancers ( 51 , 52 ). Therefore, it may be considered a target for anticancer drugs, such as imatinib ( 53 ). In the present study, the PPI network analysis suggested that PDGFRA directly interacted with ENPP3, PTPRC, TGFBI, BOC and CRYAB, indicating the key role of PDGFRA in BC.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis of key biomarkers for bladder cancer

Bai

et al. 2022

Biomed Rep

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Bladder cancer (BC) is one of the most prevalent genitourinary cancers. Despite the growing research interest in BC, the molecular mechanisms underlying its carcinogenesis remain poorly understood. The microarray datasets GSE38264 and GSE61615 obtained from the Gene Expression Omnibus (GEO) database were analyzed and differentially expressed genes (DEGs) were identified, which were then verified using a dataset from The Cancer Genome Atlas (TCGA). By taking the intersection of the two microarray datasets, the common DEGs were identified and these were selected as candidate genes associated with BC. The DEGs were further subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis, and the protein-protein interaction network was constructed. Further module analysis was performed using STRING and Cytoscape. A total of 362 DEGs were identified, including 13 hub genes, and the GO analysis revealed that these genes were mainly enriched in extracellular matrix organization, positive regulation of cell proliferation, angiogenesis and peptidyl-tyrosine phosphorylation. The expression changes of PTPRC, PDGFRA, CASQ2, TGFBI, KLRD1 and MT1X in the different datasets indicated that these genes were involved in the development of BC. Next, the differential expression of these genes was verified in the TCGA dataset, and ultimately, these 13 genes were determined to be related to the occurrence and development of BC. Finally, the cancer tissues and adjacent tissues of patients with BC were collected and subjected to reverse transcription-quantitative PCR, the results of which were consistent with the bioinformatics prediction. The present findings provide several vital genes for the clinical diagnosis and treatment of BC.

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Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis of key biomarkers for bladder cancer

Bai

et al. 2022

Biomed Rep

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“…In a cohort of 172 wild-type KIT/PDGFRA GISTs, Huss and coworkers found BRAF mutations in only 3.9% of patients [ 62 ]. More recently, several studies revealed that the BRAF (V600E) mutation could occur in 2% of GISTs carrying mutated KIT/PDGFRA with acquired resistance to imatinib [ 63 ], highlighting the possibility that the frequency of BRAF coexistence with KIT/PDGFRA mutations was under-estimated in past years due to the lack of highly sensitive analytical methods [ 64 ]. However, more recently, using a quantitative competitive allele-specific Taq-Man duplex PCR, Jašek and colleagues confirmed the concomitant but rare occurrence of BRAF/KIT and BRAF/PDGFRA mutations in GISTs [ 64 ].…”

Section: Other Mutations In Gistsmentioning

confidence: 99%

“…More recently, several studies revealed that the BRAF (V600E) mutation could occur in 2% of GISTs carrying mutated KIT/PDGFRA with acquired resistance to imatinib [ 63 ], highlighting the possibility that the frequency of BRAF coexistence with KIT/PDGFRA mutations was under-estimated in past years due to the lack of highly sensitive analytical methods [ 64 ]. However, more recently, using a quantitative competitive allele-specific Taq-Man duplex PCR, Jašek and colleagues confirmed the concomitant but rare occurrence of BRAF/KIT and BRAF/PDGFRA mutations in GISTs [ 64 ]. Accordingly, Torrence D. and colleagues have reported two spindle cell phenotype GIST cases harboring novel BRAF fusion genes arising in two young-adult women in the small bowel and esophagus.…”

Section: Other Mutations In Gistsmentioning

confidence: 99%

Emerging Targeted Therapeutic Strategies to Overcome Imatinib Resistance of Gastrointestinal Stromal Tumors

Masucci

Motti

Minopoli

et al. 2023

IJMS

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Gastrointestinal stromal tumors (GISTs) are the most common malignant mesenchymal neoplasms of the gastrointestinal tract. The gold standard for the diagnosis of GISTs is morphologic analysis with an immunohistochemical evaluation plus genomic profiling to assess the mutational status of lesions. The majority of GISTs are driven by gain-of-function mutations in the proto-oncogene c-KIT encoding the tyrosine kinase receptor (TKR) known as KIT and in the platelet-derived growth factor-alpha receptor (PDGFRA) genes. Approved therapeutics are orally available as tyrosine kinase inhibitors (TKIs) targeting KIT and/or PDGFRA oncogenic activation. Among these, imatinib has changed the management of patients with unresectable or metastatic GISTs, improving their survival time and delaying disease progression. Nevertheless, the majority of patients with GISTs experience disease progression after 2–3 years of imatinib therapy due to the development of secondary KIT mutations. Today, based on the identification of new driving oncogenic mutations, targeted therapy and precision medicine are regarded as the new frontiers for GISTs. This article reviews the most important mutations in GISTs and highlights their importance in the current understanding and treatment options of GISTs, with an emphasis on the most recent clinical trials.

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“…BRAF mutations at the exon 15 V600E hotspot are encountered in approximately 4–13% of adult wild-type GISTs and are almost mutually exclusive of KIT/PDGFRA mutations [ 67 , 68 , 69 ]. They are more frequently found in the small bowel and have variable clinical behavior [ 67 ].…”

Section: Molecular Classification Of Gistsmentioning

confidence: 99%

“…They are more frequently found in the small bowel and have variable clinical behavior [ 67 ]. Phenotypically and morphologically, BRAF -mutant GISTs are similar to KIT/PDGFRA positive GISTs [ 67 , 68 , 69 ]. More recently, BRAF fusions have been described in GISTs [ 70 ].…”

Section: Molecular Classification Of Gistsmentioning

confidence: 99%

Current Molecular Profile of Gastrointestinal Stromal Tumors and Systemic Therapeutic Implications

Mathias-Machado¹,

Jesus

Oliveira³

et al. 2022

Cancers

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Gastrointestinal stromal tumors (GISTs) are malignant mesenchymal tumors arising from the intestinal pacemaker cells of Cajal. They compose a heterogenous group of tumors due to a variety of molecular alterations. The 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. However, a smaller subset, lacking KIT and PDGFRA mutations, is considered wild-type GISTs and presents distinct molecular findings with the activation of different proliferative pathways, structural chromosomal and epigenetic changes, such as inactivation of the NF1 gene, mutations in the succinate dehydrogenase (SDH), BRAF, and RAS genes, and also NTRK fusions. Currently, a molecular evaluation of GISTs is imperative in many scenarios, aiding in treatment decisions from the (neo)adjuvant to the metastatic setting. Here, we review the most recent data on the molecular profile of GISTs and highlight therapeutic implications according to distinct GIST molecular subtypes.

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BRAF mutations in KIT/PDGFRA positive gastrointestinal stromal tumours (GISTs): Is their frequency underestimated?

Cited by 10 publications

References 28 publications

Bioinformatics analysis of key biomarkers for bladder cancer

Bioinformatics analysis of key biomarkers for bladder cancer

Emerging Targeted Therapeutic Strategies to Overcome Imatinib Resistance of Gastrointestinal Stromal Tumors

Current Molecular Profile of Gastrointestinal Stromal Tumors and Systemic Therapeutic Implications

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