Molecular characterization of metastatic exon 11 mutant gastrointestinal stromal tumors (GIST) beyond KIT/PDGFRα genotype evaluated by next generation sequencing (NGS)

Saponara, Maristella; Urbini, Milena; Astolfi, Annalisa; Indio, Valentina; Ercolani, Giorgio; Gaudio, Massimo Del; Santini, Donatella; Pirini, Maria Giulia; Fiorentino, Michelangelo; Nannini, Margherita; Lolli, Cristian; Mandrioli, Anna; Gatto, Lidia; Brandi, Giovanni; Biasco, Guido; Pinna, Antonio Daniele; Pantaleo, Maria Abbondanza

doi:10.18632/oncotarget.6278

Cited by 22 publications

(18 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Genetically, among the 27 informative cases, 19 (70%) showed LOH of at least one of the microsatellite markers on 22q11.23 including the SMARCB1/INI1 gene . In another study, four of the seven metastatic GIST cases harbored a heterozygous deletion of part or the entire arm of chromosome 22, on which SMARCB1 is located …”

Section: Mosaic Groupsmentioning

confidence: 96%

“…(74) In another study, four of the seven metastatic GIST cases harbored a heterozygous deletion of part or the entire arm of chromosome 22, on which SMARCB1 is located. (75) Ossifying fibromyxoid tumor. Ossifying fibromyxoid tumors, characterized by a lobular proliferation of small bland round cells with a peripheral shell of woven bone, are classified as tumors of uncertain differentiation.…”

Section: Mosaic Groupsmentioning

confidence: 99%

See 1 more Smart Citation

Oncogenic roles of SMARCB1/INI1 and its deficient tumors

2017

View full text Add to dashboard Cite

SMARCB1/INI1 is one of the core subunit proteins of the ATP‐dependent SWI/SNF chromatin remodeling complex, and is identified as a potent and bona fide tumor suppressor. Interactions have been demonstrated between SMARCB1/INI1 and key proteins in various pathways related to tumor proliferation and progression: the p16‐RB pathway, WNT signaling pathway, sonic hedgehog signaling pathway and Polycomb pathway. Initially, no detectable SMARCB1/INI1 protein expression was found in malignant rhabdoid tumor cells, whereas all other kinds of tumor cells and non‐tumorous tissue showed SMARCB1/INI1 protein expression. Therefore, immunohistochemical testing for the SMARCB1/INI1 antibody has been considered useful in confirming the histologic diagnosis of malignant rhabdoid tumors. However, recently, aberrant expression of SMARCB1/INI1 has been found in various tumors such as epithelioid sarcomas, schwannomatosis, synovial sarcomas, and so on. In addition, it has been reported that aberrant expression can be classified into three patterns: complete loss, mosaic expression and reduced expression. Although the various pathways related to mechanisms of tumorigenesis and tumor proliferation are complexly intertwined, the clarification of these mechanisms may contribute to therapeutic strategies in SMARCB1/INI1‐deficient tumors. In terms of pathological classifications, SMARCB1/INI1‐deficient tumors may be re‐classified by genetic backgrounds.

show abstract

Section: Mosaic Groupsmentioning

confidence: 96%

Section: Mosaic Groupsmentioning

confidence: 99%

Oncogenic roles of SMARCB1/INI1 and its deficient tumors

2017

View full text Add to dashboard Cite

show abstract

“…Anderson et al and others have suggested that KIT / PDGFRA mutations are very common events in the early stage of GIST development, and are not sufficient for GIST progression, and that other genetic changes are required for clinical manifestation . Several chromosomal changes, including deletions in chromosome arms 1p, 13q, 14q, 15q, and 22q, and gains in chromosomes 4 and 5, have been associated with malignant progression of GIST.…”

Section: Introductionmentioning

confidence: 99%

“…Several chromosomal changes, including deletions in chromosome arms 1p, 13q, 14q, 15q, and 22q, and gains in chromosomes 4 and 5, have been associated with malignant progression of GIST. However, there are no consensus genetic alterations with mutations, amplification, or deletion for GIST development . Thus, we aimed to identify driver gene alterations and the subsequent signaling pathways that drive the progression of GIST in order to develop effective therapies, particularly for TKI‐resistant patients.…”

Section: Introductionmentioning

confidence: 99%

Driver gene alterations and activated signaling pathways toward malignant progression of gastrointestinal stromal tumors

et al. 2019

View full text Add to dashboard Cite

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. AbstractMutually exclusive KIT and PDGFRA mutations are considered to be the earliest events in gastrointestinal stromal tumors (GIST), but insufficient for their malignant progression. Herein, we aimed to identify driver genes and signaling pathways relevant to GIST progression. We investigated genetic profiles of 707 driver genes, including mutations, gene fusions, copy number gain or loss, and gene expression for 65 clinical specimens of surgically dissected GIST, consisting of six metastatic tumors and 59 primary tumors from stomach, small intestine, rectum, and esophagus. Genetic alterations included oncogenic mutations and amplification-dependent expression enhancement for oncogenes (OG), and loss of heterozygosity (LOH) and expression reduction for tumor suppressor genes (TSG). We assigned activated OG and inactivated TSG to 27 signaling pathways, the activation of which was compared between malignant GIST (metastasis and high-risk GIST) and less malignant GIST (low-and very low-risk GIST). Integrative molecular profiling indicated that a greater incidence of genetic alterations of driver genes was detected in malignant GIST (96%, 22 of 23) than in less malignant GIST (73%, 24 of 33). Malignant GIST samples groups showed mutations, LOH, and aberrant expression dominantly in driver genes associated with signaling pathways of PI3K (PIK3CA, AKT1, and PTEN) and the cell cycle (RB1, CDK4, and CDKN1B). Additionally, we identified potential PI3K-related genes, the expression of which was upregulated (SNAI1 and TPX2) or downregulated (BANK1) in malignant GIST. Based on our observations, we propose that inhibition of PI3K pathway signals Correspondence

show abstract

“…With the development of nextgeneration sequencing (NGS), a technology capable of simultaneously sequencing millions of DNA fragments without previous sequence knowledge, increases in the positive rate of ctDNA mutation detection have become feasible (10). NGS has been widely used in genetic analysis of patients with various tumors including GIST because of the advantages of higher reliability and lower costs (10,11).…”

Section: Introductionmentioning

confidence: 99%

Clinical Application of Circulating Tumor DNA in the Genetic Analysis of Patients with Advanced GIST

Chen

Shao³

et al. 2018

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumor of digestive tract. In the past, tissue biopsy was the main method for the diagnosis of GISTs. Although, circulating tumor DNA (ctDNA) detection by next-generation sequencing (NGS) may be a feasible and replaceable method for diagnosis of GISTs. We retrospectively analyzed the data for ctDNA and tissue DNA detection from 32 advanced GIST patients. We found that NGS obviously increased the positive rate of ctDNA detection. ctDNA detection identified rare mutations that were not detected in tissue DNA detection. Tumor size and Ki-67 were significant influencing factors of the positive rate of ctDNA detection and concordance between ctDNA and tissue DNA detection. In all patients, the concordance rate between ctDNA and tissue DNA detection was 71.9%, with moderate concordance, but the concordance was strong for patients with tumor size > 10 cm or Ki-67 > 5%. Tumor size, mitotic figure, Ki-67, and ctDNA mutation type were the significant influencing factors of prognosis, but only tumor size and ctDNA mutation type, were the independent prognostic factors for advanced GIST patients. We confirmed that ctDNA detection by NGS is a feasible and promising method for the diagnosis and prognosis of advanced GIST patients.

show abstract

Molecular characterization of metastatic exon 11 mutant gastrointestinal stromal tumors (GIST) beyond KIT/PDGFRα genotype evaluated by next generation sequencing (NGS)

Cited by 22 publications

References 51 publications

Oncogenic roles of SMARCB1/INI1 and its deficient tumors

Oncogenic roles of SMARCB1/INI1 and its deficient tumors

Driver gene alterations and activated signaling pathways toward malignant progression of gastrointestinal stromal tumors

Clinical Application of Circulating Tumor DNA in the Genetic Analysis of Patients with Advanced GIST

Contact Info

Product

Resources

About