Prognostic significance of <i>p53</i> gene mutations and protein overexpression in localized gastrointestinal stromal tumours

Ryu, Min‐Hee; Kang, Yoon‐Koo; Jang, Se Jin; Kim, T W; Lee, H; Kim, J S; Park, Y H; Lee, S S; Ryoo, Baek‐Yeol; Chang, Heung Moon; Lee, J L; Yook, Jeong Hwan; Kim, B S; Lee, J S

doi:10.1111/j.1365-2559.2007.02797.x

Cited by 21 publications

(12 citation statements)

References 35 publications

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“…We found mutations in 16.4% of cases, selected on the basis of p53 protein expression. In agreement with our results, Ryu et al showed TP53 mutations in 22% of the GISTs with high p53 protein expression (24). The low percentage of mutation in high p53 expressers might reflect its late occurrence in a subpopulation of cells, for which direct sequencing might not be able to identify it.…”

Section: Discussionsupporting

confidence: 81%

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: Discussionsupporting

confidence: 81%

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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“…Our meta-analysis showed that p53 expression appeared more often in recurred or metastasized GIST (malignant group) than in tumors with disease-free follow-up (benign group). Furthermore, p53 expression was significantly associated with the established prognostic criteria (NIH system), and was consistent with most previous GIST studies (6,(11)(12)(13)15,(16)(17)(18)(19). NIH I+H showed more positivity with p53 than NIH VL+L tumors.…”

Section: Discussionsupporting

confidence: 76%

“…A total of 19 publications met the inclusion criteria (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). The studies by Chou et al, Padilla et al, Romeo et al and Kwon et al were excluded due to insufficient information to calculate an OR (25)(26)(27)(28), and the study by Sakurai et al was also excluded since they used telomerase activity as the criteria for measuring the malignant risk of GIST (29).…”

Section: Study Characteristicsmentioning

confidence: 99%

Predictive value of p53 expression in the risk of malignant gastrointestinal stromal tumors: Evidence from 19 studies

Zong

Chen

Jiang

et al. 2011

Experimental and Therapeutic Medicine

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Abstract. The current published data on p53 expression and its predictive value in the risk of malignant gastrointestinal stromal tumors (GIST) has are inconclusive. To derive a more precise estimation of the correlation between p53 and the biological behavior of GIST, a meta-analysis was performed. Studies were identified by searching PubMed and Embase. Inclusion criteria were GIST patients, and the evaluation of p53 expression and risk of malignancy. The odds ratio (OR) for a positive rate of p53 in the benign group vs. that in the malignant group and the ORs for the positive rate of p53 in the National Institutes of Health (NIH) very low risk + low risk group (VL+L) vs. the NIH intermediate risk + high risk (I+H) group were calculated with a 95% confidence interval (CI) for each study as an estimation of the predictive value of p53. A total of 19 studies including 1163 patients were involved in this meta-analysis. The overall OR for the positive rate of p53 in the malignant group vs. the benign group revealed that significantly elevated risks of positive p53 in the malignant group were achieved (OR 0.14, 95% CI: 0.06-0.31, P<0.00001, P heterogeneity =0.86). Moreover, significantly elevated risks of correlation between p53 expression and the NIH I+H group were achieved in the comparison of the NIH VL+L group vs. the NIH I+H group (OR, 0.25; 95% CI, 0.17-0.38; P<0.00001, P heterogeneity =0.04). The results indicate that p53 expression correlates with poor prognosis in GIST and has a close relationship within the NIH I+H group.

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“…Larger series, however, have found both size and mitotic rate to be independent predictors. 19,28 This discrepancy may be explained by review of the hazard ratio as the hazard ratio for mitotic count >10/ 50HPF is high (HR 14.6-45.9) and is typically several fold larger than that for size >10 cm (HR 2.5-20.9). 19,29 Achieving R0 resection is vital as recurrent disease fails to be indefinitely controlled with tyrosine kinase inhibitors.…”

Section: Discussionmentioning

confidence: 94%

Surgical Therapy for Gastrointestinal Stromal Tumours of the Upper Gastrointestinal Tract

Das

Wilson

Biankin

et al. 2009

Journal of Gastrointestinal Surgery

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Prognostic significance of p53 gene mutations and protein overexpression in localized gastrointestinal stromal tumours

Abstract: Alterations in p53 were more commonly observed in localized GISTs at higher risk of relapse. This suggests that they are significant as an independent, poor prognostic factor.

Cited by 21 publications

References 35 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

Predictive value of p53 expression in the risk of malignant gastrointestinal stromal tumors: Evidence from 19 studies

Surgical Therapy for Gastrointestinal Stromal Tumours of the Upper Gastrointestinal Tract

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