<i>KIT</i> and <i>PDGFRA</i> Mutations and the Risk of GI Stromal Tumor Recurrence

Joensuu, Heikki; Rutkowski, Piotr; Nishida, Toshirou; Steigen, Sonja Eriksson; Brabec, Peter; Plank, L; Nilsson, Bengt; Braconi, Chiara; Bordoni, Andrea; Magnússon, Magnús K.; Šufliarský, Jozef; Federico, Massimo; Jonasson, Jón G.; Hostein, Isabelle; Bringuier, Pierre Paul; Emile, Jean François

doi:10.1200/jco.2014.57.4970

Cited by 152 publications

(177 citation statements)

References 35 publications

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“…7,15,18,21,31 The higher PDGFRA mutation frequency observed in gastric GISTs is in accordance with the better prognosis observed for this type of tumor. 12,30,32 Our study revealed the potential prognostic relevance of the type and position of KIT mutations in untreated resected gastric GISTs, in addition to classic pathological criteria such as dimension, mitosis, Miettinen risk stratification, ulceration and necrosis.…”

Section: Discussionsupporting

confidence: 67%

Gastric GISTs: Analysis of c-Kit, PDGFRA and BRAF mutations in relation to prognosis and clinical pathological characteristics of patients – A GIRCG study

Capelli

Petracci

Quagliuolo

et al. 2016

European Journal of Surgical Oncology (EJSO)

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Background: Gastric gastrointestinal stromal tumors (GISTs) represent a subgroup of GISTs with a better prognosis than those located in other areas. In this retrospective study we performed a molecular characterization of a large series of patients with gastric GISTs in relation to clinicalepathological characteristics and prognosis. Methods: DNA was extracted from paraffin-embedded sections from 221 gastric GIST patients submitted to surgery. Exons 9, 11, 13 and 17 of KIT, exons 12 and 18 of PDGFRA and exons 11 and 15 of BRAF were analyzed by direct sequencing. Cox regression analysis adjusted for clinicalepathological factors was performed to evaluate KIT and PDGFRA mutations in relation to the composite endpoint of relapse or death. Results: KIT and PDGFRA mutations were observed in 119 (53.8%) and 56 (25.3%) patients, respectively, whereas 46 (20.8%) patients had wild type (wt) disease. Univariable analyses showed that a high Miettinen risk category and the presence of ulceration and KIT deletions

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Section: Discussionsupporting

confidence: 67%

Gastric GISTs: Analysis of c-Kit, PDGFRA and BRAF mutations in relation to prognosis and clinical pathological characteristics of patients – A GIRCG study

Capelli

Petracci

Quagliuolo

et al. 2016

European Journal of Surgical Oncology (EJSO)

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“…Previous studies have demonstrated that activating mutations in the receptor tyrosine kinases KIT and PDGFRA are critical for the pathogenesis of GISTs (23)(24)(25). Recent studies have shown the important function of ETS variant 1 (ETV1), an ETS family transcriptional factor, in the progression of GISTs, and suggested that targeting both KIT and ETV1 may be effective for the treatment of this type of tumor (26,27).…”

Section: Discussionmentioning

confidence: 99%

AMPD3 is associated with the malignant characteristics of gastrointestinal stromal tumors

et al. 2016

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Abstract. Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the gastrointestinal tract. It is well known that activating mutations in the receptor tyrosine kinases KIT and platelet-derived growth factor receptor-α have essential roles in the pathogenesis of GISTs. The activation of these receptor protein kinases triggers multiple signaling pathways that promote cell proliferation and survival; however, the exact mechanism by which the activation of these kinases promotes the progression of GISTs remains uncertain. The aim of the present was to search for genes that are associated with the progression of GIST. The present study used reverse transcription-quantitative polymerase chain reaction to demonstrate that adenosine monophosphate deaminase 3 (AMPD3) was highly expressed in GISTs. Furthermore, transfection of GIST-T1 cells with KIT-specific small interfering RNA (siRNA) demonstrated that the expression of AMPD3 was dependent on KIT expression, while the depletion of AMPD3 in human GIST-T1 cells using AMPD3-specific siRNA resulted in the suppression of cell migration and invasion. In addition, AMPD3 depletion sensitized GIST-T1 cells to the tyrosine kinase inhibitor imatinib. The results of the present suggested that the combined inhibition of tyrosine kinases and AMPD3 may be effective for the treatment of GISTs.

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“…The Contica GIST study (15), clearly showed that gastric GIST with a KIT del 557-558 had an inferior disease free survival compared to other mutants. A larger study, comprising 11 population based series (n=3,067; mutation analysis-1505), but untreated with IM, concluded that patients with PDGFRA mutations and those with KIT exon 11 duplication/single codon deletion mutations have a favorable recurrence free survival (RFS) with surgery alone (20). Conversely, in the adjuvant setting in operated tumors, mutation status has not replaced standard criteria with regard to the need for adjuvant IM, although data from long term follow up of the ACOSOG Z9001 Trial has suggested that KIT exon 11 deletions had maximal benefit from 1 year of adjuvant IM compared to other molecular subsets (21).…”

Section: Discussionmentioning

confidence: 99%

Early outcomes of exon 11 mutants in GIST treated with standard dose Imatinib

et al. 2017

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Background: The exon 11 KIT mutant gastrointestinal stromal tumors (GIST) is a heterogeneous cohort with variable biological behavior based on different mutational subtypes. Methods:Patients with histologically proven GIST with KIT exon 11 mutations were selected from a prospectively maintained database, and evaluated for clinical characteristics and event free survival (EFS). Patients were divided into mutations upstream to codon 557 (G1), mutations involving codon 557-558 (G2) and mutation downstream to codon 558 (G3).Results: A total of 90 patients satisfied the inclusion criteria for study. Substitutions, indels and duplications were seen in 23 patients. Deletions were seen in 67 patients, of which 44 patients had large deletions (>6 base pairs), while 23 has small deletions (<6 base pairs). Complex mutations were seen in 15 patients. G2 mutations were noted in 33 patients, while G1 and G3 mutations were seen 32 and 25 patients respectively. With a median follow-up of 26 months, estimated median EFS for the entire cohort was 55 months. The G2 cohort had an inferior EFS compared to the G1 and G3 cohorts (46 vs. 55 months), but this did not achieve statistical significance (univariate analysis: P=0.075). On multivariate analysis, patients undergoing radical intent surgery vs. no surgery (58 vs. 55 months; P=0.005) and G1 or G3 vs. G2 cohort (P=0.058) showed trend towards improved EFS. Conclusions:In patients with GIST exon 11 codon 557-558 mutation subset there is a trend towards an inferior survival even when treated with imatinib mesylate (IM).

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KIT and PDGFRA Mutations and the Risk of GI Stromal Tumor Recurrence

Cited by 152 publications

References 35 publications

Gastric GISTs: Analysis of c-Kit, PDGFRA and BRAF mutations in relation to prognosis and clinical pathological characteristics of patients – A GIRCG study

Gastric GISTs: Analysis of c-Kit, PDGFRA and BRAF mutations in relation to prognosis and clinical pathological characteristics of patients – A GIRCG study

AMPD3 is associated with the malignant characteristics of gastrointestinal stromal tumors

Early outcomes of exon 11 mutants in GIST treated with standard dose Imatinib

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