The Identity of PDGFRA D842V-Mutant Gastrointestinal Stromal Tumors (GIST)

Rizzo, Alessandro; Pantaleo, Maria Abbondanza; Astolfi, Annalisa; Indio, Valentina; Nannini, Margherita

doi:10.3390/cancers13040705

Cited by 17 publications

(11 citation statements)

References 40 publications

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“…Sunitinib and regorafenib are approved as second- and third-line treatments for patients with GIST who develop resistance to imatinib ( 16 , 17 ). However, about 5%–10% of GIST have platelet-derived growth factor receptor (PDGFRA) mutations, which lead to resistance to imatinib and sunitinib ( 18 ). Some GIST patients lack KIT and PDGFRA mutations, and approximately 20%–40% of GISTs deficient in KIT and PDGFRA mutations show succinate dehydrogenase (SDH) complex defects, and the therapeutic role of TKIs in patients with SDH-deficient GIST remains controversial.…”

Section: Discussionmentioning

confidence: 99%

The relationship between Ki-67 expression and imaging signs and pathological features in GISTs

Xiao

Zhang²,

Wang³

et al. 2023

Front. Surg.

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IntroductionTo investigate the correlations between the Ki-67 index and plain-scan computerized tomography (CT) signs and pathological features of gastrointestinal stromal tumor (GIST) tissue.Materials and methodsData from 186 patients with GIST diagnosed by pathology and immunohistochemistry (IHC) in Peking University First Hospital from May 2016 to May 2022 were analyzed. The patients were divided into two groups: Ki-67 ≤5% and >5%. Correlation analysis, univariate and multivariate Logistic regression analysis were used to explore the correlations between CT signs, pathological features, and Ki-67 expression.ResultsUnivariate indicators correlated with the Ki-67 index were mitotic count, pathological grade, tumor hemorrhage, tumor necrosis, tumor size, and tumor density. Multivariate Logistic regression indicated that the mitotic count [odds ratio (OR) 10.222, 95% confidence interval (CI) 4.312–31.039], pathological grade (OR 2.139, 95% CI 1.397–3.350), and tumor size (OR 1.096, 95% CI 1.020–1.190) were independently associated with the Ki-67 expression level. The concordance indexes (C-index) for the pathological features and CT signs models were 0.876 (95% CI 0.822–0.929) and 0.697 (95% CI 0.620–0.774), respectively, with positive predictive values of 93.62% and 58.11% and negative predictive values of 81.29% and 75.89%, respectively. After internal verification by the Bootstrap method, the fitting degree of the pathological features model was found to be better than that of the CT signs model.ConclusionMitotic count, pathological risk grading, and tumor size are independent risk factors correlating with high Ki-67 index. These results indicate that the Ki-67 index reflects tumor malignancy and can predict recurrence and metastasis of GIST.

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Section: Discussionmentioning

confidence: 99%

The relationship between Ki-67 expression and imaging signs and pathological features in GISTs

Xiao

Zhang²,

Wang³

et al. 2023

Front. Surg.

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“…PDGFRA mutations occurring at exons 18 and 12 accounted for 5% of all mutations. The mutation comprising a substitution at position 842 in the A-loop of an aspartic acid (D) with a valine (V) in exon 18 confers primary resistance to imatinib and sunitinib but sensitivity to avapritinib [ 26 , 27 ]. Somatic mutations in C-KIT are usually found in exon 11, which might confer sensitivity to imatinib [ 1 , 2 , 28 ].…”

Section: Discussionmentioning

confidence: 99%

Small Gastric Stromal Tumors: An Underestimated Risk

Guo

Yang

et al. 2022

Cancers

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Background and Objectives: Small gastrointestinal stromal tumors (GISTs) are defined as tumors less than 2 cm in diameter, which are often found incidentally during gastroscopy. There is controversy regarding the management of small GISTs, and a certain percentage of small GISTs become malignant during follow-up. Previous studies which used Sanger targeted sequencing have shown that the mutation rate of small GISTs is significantly lower than that of large tumors. The aim of this study was to investigate the overall mutational profile of small GISTs, including those of wild-type tumors, using whole-exome sequencing (WES) and Sanger sequencing. Methods: Thirty-six paired small GIST specimens, which were resected by endoscopy, were analyzed by WES. Somatic mutations identified by WES were confirmed by Sanger sequencing. Sanger sequencing was performed in an additional 38 small gastric stromal tumor samples for examining hotspot mutations in KIT, PDGFRA, and BRAF. Results: Somatic C-KIT/PDGFRA mutations accounted for 81% of the mutations, including three novel mutation sites in C-KIT at exon 11, across the entire small gastric stromal tumor cohort (n = 74). In addition, 15% of small GISTs harbored previously undescribed BRAF-V600E hotspot mutations. No significant correlation was observed among the genotype, pathological features, and clinical classification. Conclusions: Our data revealed a high overall mutation rate (~96%) in small GISTs, indicating that genetic alterations are common events in early GIST generation. We also identified a high frequency of oncogenic BRAF-V600E mutations (15%) in small GISTs, which has not been previously reported.

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“…Other activating mutations can occur, less frequently, in exons 12 and 14 [ 23 , 44 ]. Although the majority of PDGFRA mutations occur at the somatic level, germline PDGFRA pathogenic variants cause a rare hereditary syndrome characterized by an increased susceptibility to multiple gastrointestinal mesenchymal tumors, including GISTs [ 45 ]. Due to the lack of interstitial Cajal cell (ICC) hyperplasia in GISTS arising within this syndrome, as opposed to what has been observed in KIT germline mutant GISTs, it has been recently hypothesized that GISTs bearing PDGFRA mutations, which are mutually exclusive to KIT mutations, may originate from telocytes instead of ICCs [ 46 ].…”

Section: Diagnosis and Molecular Characterizationmentioning

confidence: 99%

Molecular Tailored Therapeutic Options for Advanced Gastrointestinal Stromal Tumors (GISTs): Current Practice and Future Perspectives

Catalano

Cremante

Dalmasso

et al. 2023

Cancers

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Gastrointestinal stromal tumors (GISTs) are one of the most common mesenchymal tumors characterized by different molecular alterations that lead to specific clinical presentations and behaviors. In the last twenty years, thanks to the discovery of these mutations, several new treatment options have emerged. This review provides an extensive overview of GISTs’ molecular pathways and their respective tailored therapeutic strategies. Furthermore, current treatment strategies under investigation and future perspectives are analyzed and discussed.

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The Identity of PDGFRA D842V-Mutant Gastrointestinal Stromal Tumors (GIST)

Cited by 17 publications

References 40 publications

The relationship between Ki-67 expression and imaging signs and pathological features in GISTs

The relationship between Ki-67 expression and imaging signs and pathological features in GISTs

Small Gastric Stromal Tumors: An Underestimated Risk

Molecular Tailored Therapeutic Options for Advanced Gastrointestinal Stromal Tumors (GISTs): Current Practice and Future Perspectives

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