Patterns of gene amplification in gastrointestinal stromal tumors (GIST)

Tornillo, Luigi; Duchini, Giacomo; Carafa, Vincenza; Lugli, Alessandro; Dirnhofer, Stefan; Vizio, Dolores Di; Boscaino, Amedeo; Russo, Raffaella; Tapia, Coya; Schneider‐Stock, Regine; Sauter, Guido; Insabato, Luigi; Terracciano, Luigi

doi:10.1038/labinvest.3700284

Cited by 56 publications

(52 citation statements)

References 74 publications

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“…High expression of these three oncogenes was infrequent in our study. Accordingly, amplification of the corresponding chromosomal regions (11q13, 12q14, and 12q14.3-q15, respectively, for CCND1, CDK4, and MDM2) is not a frequent event in GIST (5,28).…”

Section: Discussionmentioning

confidence: 99%

Cell Cycle/Apoptosis Molecule Expression Correlates with Imatinib Response in Patients with Advanced Gastrointestinal Stromal Tumors

Romeo

Dębiec‐Rychter²,

Glabbeke³

et al. 2009

Clinical Cancer Research

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Purpose: Altered expression of cell cycle/apoptosis key regulators may promote tumor progression, reflect secondary genetic/epigenetic events, and impair the effectiveness of therapy. Their expression pattern might then identify gastrointestinal stromal tumor (GIST) patient subgroups with different response to imatinib and elucidate novel therapeutic targets. Experimental Design: Immunohistochemical evaluation of expression of p53, p16, p21, CHK2, CCND1, BCL2, CDK4, and MDM2 was done on 353 histologically validated GIST patients enrolled into a European/Australasian phase III trial. TP53 was screened for mutations in cases with presumptive nonfunctional protein; that is, high p53 and low expression of the two downstream molecules p21 and MDM2. Results were correlated with clinicopathologic data, KIT/PDGFRA mutation status, and imatinib dosage. Results: Frequent impaired expression was found for BCL2 (78%), CHK2 (53%), p53 (50%), and p16 (47%). Stomach-originating GISTs showed significantly lower expression of p21, p16, and BCL2. KIT/PDGFRA wild-type GISTs had significant lower expression of CDK4. Eighty-eight percent of the high p53 expressers show low downstream target activation, indicating a nonfunctional p53 route. Of these high p53 expressers, 16.4% harbor a detectable TP53 mutation. Multivariate analysis, including previously identified markers, showed an independent effect of p53 and p16 on progression-free survival (PFS). Patients with high level of CHK2 and p21 showed significantly better PFS upon a high-dose regimen. Conclusions: Impaired p53, p16, BCL2, and CHK2 expression is common in advanced GISTs. Distinct patterns of expression correlate with tumor site, genotype, and PFS. Cell cycle/apoptosis maintenance is instrumental for optimal response to imatinib.Gastrointestinal stromal tumors are the most frequent gastrointestinal mesenchymal tumors with an incidence of 10 to 14.5 new cases per million inhabitants (1). The majority show oncogenic activating mutations of KIT tyrosine kinase (2) and a subset of platelet-derived factor receptor α (PDGFRA; ref. 3). Mutation-imposed constitutive signaling promotes survival and proliferation of tumor cells ( Fig. 1A; ref. 2). Apart from KIT/PDGFRA mutations, other genetic/epigenetic changes occur

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Section: Discussionmentioning

confidence: 99%

Cell Cycle/Apoptosis Molecule Expression Correlates with Imatinib Response in Patients with Advanced Gastrointestinal Stromal Tumors

Romeo

Dębiec‐Rychter²,

Glabbeke³

et al. 2009

Clinical Cancer Research

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“…[102][103][104] Likewise, amplifications of MDM2 and CCND1 (cyclin D1), although uncommon in GISTs, are associated with malignancy. 105 …”

Section: Micro-gistsmentioning

confidence: 99%

Gastrointestinal stromal tumors: what do we know now?

2014

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Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the GI tract, arising from the interstitial cells of Cajal, primarily in the stomach and small intestine. They manifest a wide range of morphologies, from spindle cell to epithelioid, but are immunopositive for KIT (CD117) and/or DOG1 in essentially all cases. Although most tumors are localized at presentation, up to half will recur in the abdomen or spread to the liver. The growth of most GISTs is driven by oncogenic mutations in either of two receptor tyrosine kinases: KIT (75% of cases) or PDGFRA (10%). Treatment with tyrosine kinase inhibitors (TKIs) such as imatinib, sunitinib, and regorafenib is effective in controlling unresectable disease; however, drug resistance caused by secondary KIT or PDGFRA mutations eventually develops in 90% of cases. Adjuvant therapy with imatinib is commonly used to reduce the likelihood of disease recurrence after primary surgery, and for this reason assessing the prognosis of newly resected tumors is one of the most important roles for pathologists. Approximately 15% of GISTs are negative for mutations in KIT and PDGFRA. Recent studies of these so-called wild-type GISTs have uncovered a number of other oncogenic drivers, including mutations in neurofibromatosis type I, RAS genes, BRAF, and subunits of the succinate dehydrogenase complex. Routine genotyping is strongly recommended for optimal management of GISTs, as the type and dose of TKI used for treatment is dependent on the mutation identified.

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“…Sections (4 Am) from the TMA paraffin block were transferred to an adhesive-coated slide system. Standard indirect immunoperoxidase procedures were used for immunohistochemistry after antigen retrieval in citrate buffer (pH 6.0) as described (26). Nuclear localization of EGFR was analyzed quantitatively using the automated quantitative analysis (AQUA) system (27).…”

Section: Methodsmentioning

confidence: 99%

The Phosphoinositide Kinase PIKfyve Mediates Epidermal Growth Factor Receptor Trafficking to the Nucleus

et al. 2007

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ErbB receptor tyrosine kinases can transit to nuclei in tumor cells, where they have been shown to regulate gene expression as components of transcriptional complexes. Quantitative analysis of a human bladder cancer tissue microarray identified nuclear epidermal growth factor receptor (EGFR) in tumor cells and also showed an increased frequency of this histologic feature in cancer relative to normal tissues. This observation suggests a potential role for nuclear EGFR in bladder cancer. We confirmed that EGFR could be induced to transit to nuclei in cultured human bladder cancer cells in response to the urothelial cell growth factor and EGFR ligand heparin-binding EGF-like growth factor (HB-EGF). Mass spectrometric analysis of EGFR immune complexes from a transitional carcinoma cell line (TCCSUP) identified the phosphoinositide kinase, PIKfyve, as a potential component of the EGFR trafficking mechanism. RNA silencing indicated that PIKfyve is a mediator of HB-EGF-stimulated EGFR nuclear trafficking, EGFR binding to the cyclin D1 promoter, and cell cycle progression. These results identify a novel mediator of the EGFR transcription function and further suggest that nuclear EGFR and the lipid kinase PIKfyve may play a role in bladder oncogenesis.

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Patterns of gene amplification in gastrointestinal stromal tumors (GIST)

Cited by 56 publications

References 74 publications

Cell Cycle/Apoptosis Molecule Expression Correlates with Imatinib Response in Patients with Advanced Gastrointestinal Stromal Tumors

Cell Cycle/Apoptosis Molecule Expression Correlates with Imatinib Response in Patients with Advanced Gastrointestinal Stromal Tumors

Gastrointestinal stromal tumors: what do we know now?

The Phosphoinositide Kinase PIKfyve Mediates Epidermal Growth Factor Receptor Trafficking to the Nucleus

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