Correlation between P53 expression and malignant risk of gastrointestinal stromal tumors: Evidence from 9 studies

Zong, Liang; Chen, P.; Xu, Yingying

doi:10.1016/j.ejso.2011.12.012

Cited by 14 publications

(8 citation statements)

References 34 publications

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“…For several decades, the role of TP53 deregulation in carcinogenesis has been studied in human cancers and associated with both the loss of tumorsuppressing function and the oncogenic function (32). The negative prognostic role of TP53 gene overexpression and its correlation with the increased malignant risk in GIST have been already described (33). However, to our knowledge, specific TP53 mutations have never been described in GIST patients.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Analysis Identifies MEN1 and MAX Mutations and a Neuroendocrine-Like Molecular Heterogeneity in Quadruple WT GIST

Pantaleo

Urbini

Indio

et al. 2017

Molecular Cancer Research

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Quadruple wild-type (WT) gastrointestinal stromal tumor (GIST) is a genomic subgroup lacking KIT/PDGFRA/RAS pathway mutations, with an intact succinate dehydrogenase (SDH) complex. The aim of this work is to perform a wide comprehensive genomic study on quadruple WT GIST to improve the characterization of these patients. We selected 14 clinical cases of quadruple WT GIST, of which nine cases showed sufficient DNA quality for whole exome sequencing (WES). NF1 alterations were identified directly by WES. Gene expression from whole transcriptome sequencing (WTS) and miRNA profiling were performed using fresh-frozen, quadruple WT GIST tissue specimens and compared with SDH and KIT/PDGFRA-mutant GIST. WES identified an average of 18 somatic mutations per sample. The most relevant somatic oncogenic mutations identified were in TP53, MEN1, MAX, FGF1R, CHD4, and CTDNN2. No somatic alterations in NF1 were identified in the analyzed cohort. A total of 247 mRNA transcripts and 66 miRNAs were differentially expressed specifically in quadruple WT GIST. Overexpression of specific molecular markers (COL22A1 and CALCRL) and genes involved in neural and neuroendocrine lineage (ASCL1, Family B GPCRs) were detected and further supported by predicted miRNA target analysis. Quadruple WT GIST show a specific genetic signature that deviates significantly from that of KIT/PDGFRA-mutant and SDH-mutant GIST. Mutations in MEN1 and MAX genes, a neural-committed phenotype and upregulation of the master neuroendocrine regulator ASCL1, support a genetic similarity with neuroendocrine tumors, with whom they also share the great variability in oncogenic driver genes. This study provides novel insights into the biology of quadruple WT GIST that potentially resembles neuroendocrine tumors and should promote the development of specific therapeutic approaches. .

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Section: Discussionmentioning

confidence: 99%

Genome-Wide Analysis Identifies MEN1 and MAX Mutations and a Neuroendocrine-Like Molecular Heterogeneity in Quadruple WT GIST

Pantaleo

Urbini

Indio

et al. 2017

Molecular Cancer Research

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“…Recent studies reported that those patients with secondary imatinib resistance are through polyclonal acquisition of second-site mutations in the kinase domain. Regardless of this, it has been proved that constitutive KIT/PDGFR activation promotes proliferation and inhibits apoptosis of neoplastic cells through the CCRP signaling pathway [55]. An alteration in CCRP is often implicated in the pathogenesis and tumor progression of various types of tumors.…”

Section: Discussionmentioning

confidence: 99%

Prognostic value of KIT/PDGFRA mutations in gastrointestinal stromal tumors: a meta-analysis

Zong

Chen

2014

World J Surg Onc

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BackgroundThe postulated relationship between KIT/PDGFRA mutations and their prognostic value in gastrointestinal stromal tumors (GISTs) has generated intense attention during the past decade, despite the fact that a great deal of studies have been conducted on this subject. To provide a strong quantitative estimate of this postulated relationship, we carried out a meta-analysis which combined, compared, and summarized the results of existing relevant studies.MethodsStudies were identified by searching databases and reviewing citations in relevant articles. Of 48 potentially relevant studies, we combined individual patient data from 18 studies which involved 1,487 patients with GISTs, by which we made a comparison between the positive KIT mutation subgroup and the negative KIT mutation subgroup (PDGFRA mutation and wild type). We tabulated and analyzed the patient characteristics from each study, including general information such as age and gender, histopathological parameters, and clinical follow-up outcomes.ResultsKIT mutations, compared with PDGFRA mutations and wild type, showed a marked increased risk not only for tumor size (>5 cm) but also for higher mitotic activity (>5), suggesting that KIT mutations significantly correlated with the National Comprehensive Cancer Network (NCCN) high risk or National Institutes of Health (NIH) high risk (1.74 (95% CI, 1.20 to 2.53) and 2.00 (95% CI, 1.08 to 3.68), respectively). Moreover, higher recurrence and metastasis was observed in GISTs with KIT mutations, revealing its closer correlation with clinical malignant risk (P <0.001 for each, with odds ratio (OR) of 2.06 (95%, 1.37 to 3.11) and 2.77 (95%, 1.64 to 4.67), respectively). High risk or malignant GISTs with KIT mutations had a significantly poorer prognosis, as measured by 3-year overall survival, compared to those with PDGFRA mutations and wild type (0.47 (95% CI, 0.25 to 0.90)).ConclusionsKIT mutations, compared with PDGFRA mutations and wild type, represent a poorer prognostic marker in high risk or malignant GISTs.

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“…Numerous studies have used correlations among biological behaviors to predict the prognosis of GIST, including mitotic count, [ 6 ] tumor size, [ 7 ] KIT mutations, [ 8 ] predominant cell type, [ 9 ] cellular density, [ 10 ] p53, [ 11 ] and other factors. In 2001, GIST was categorized by National Institutes of Health (NIH) into 4 groups on the basis of the 2 parameters, tumor size and mitotic count: very low risk, low risk, intermediate risk, and high risk (Table 1 ).…”

Section: Introductionmentioning

confidence: 99%

Ki67 is a biological marker of malignant risk of gastrointestinal stromal tumors

Zhou

Chen

et al. 2017

Medicine

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Background:Ki67 is a good marker of cell proliferation in a variety of tumors. High ki67 levels are usually associated with poor prognosis. However, the relationship between Ki67 expression and the risk of malignancy of gastrointestinal stromal tumors (GISTs) is still poorly defined. The current meta-analysis was initiated to address this issue.Methods:Studies reporting Ki67 expression and the risk of malignancy in GIST were found by searching Cochrane Library, PubMed, Medline, and Embase until October 31, 2016. A total of 9 studies involving 982 patients were included. Pooled odds ratio (OR) estimates and 95% confidence intervals (CIs) were calculated using a fixed-effect model.Results:Meta-analysis showed no significant difference in the incidence of Ki67 overexpression between the very low NIH group and the low NIH group (OR: 0.66, 95% CI: 0.25–1.76; P = .41, Pheterogeneity = .25). However, the incidence of Ki67 overexpression gradually increased from the low NIH group to the high NIH group (OR: 0.46, 95% CI: 0.27–0.80; P = .005, Pheterogeneity = .13) and (OR: 0.22, 95% CI: 0.15–0.34; P < .00001, Pheterogeneity = .33).Conclusions:There were more GIST patients with Ki67 overexpression in the intermediate and high NIH groups than in the low NIH group. Ki67 overexpression may be a useful marker of the risk of malignant GIST transformation.

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Correlation between P53 expression and malignant risk of gastrointestinal stromal tumors: Evidence from 9 studies

Cited by 14 publications

References 34 publications

Genome-Wide Analysis Identifies MEN1 and MAX Mutations and a Neuroendocrine-Like Molecular Heterogeneity in Quadruple WT GIST

Genome-Wide Analysis Identifies MEN1 and MAX Mutations and a Neuroendocrine-Like Molecular Heterogeneity in Quadruple WT GIST

Prognostic value of KIT/PDGFRA mutations in gastrointestinal stromal tumors: a meta-analysis

Ki67 is a biological marker of malignant risk of gastrointestinal stromal tumors

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