Distinct Gene Expression–Defined Classes of Gastrointestinal Stromal Tumor

Yamaguchi, Umio; Nakayama, Robert; Honda, Kazufumi; Ichikawa, Hitoshi; Hasegawa, Tadashi; Shitashige, Miki; Ono, M.; Shoji, Ayako; Sakuma, Tomohiro; Kuwabara, Hideya; Shimada, Yasuhiro; Sasako, Mitsuru; Shimoda, Tadakazu; Kawai, Akira; Hirohashi, Setsuo; Yamada, Tesshi

doi:10.1200/jco.2007.14.2331

Cited by 113 publications

(97 citation statements)

References 33 publications

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“…Low expression of ING4 correlated with poor prognosis of GISTs. In addition, a recent study has identified CD26 associated with the increased risk of postoperative recurrence warrants diagnostic application, but only CD26 is associated with the outcome of the gastric GISTs [35]. In our results, tumor location has statistical significance in different ING4 expression groups.…”

Section: Discussionsupporting

confidence: 69%

Low ING4 protein expression detected by paraffin-section immunohistochemistry is associated with poor prognosis in untreated patients with gastrointestinal stromal tumors

et al. 2013

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Background Inhibitor of growth 4 (ING4) has deserved attention as a tumor suppressor gene in many malignant tumors. In our study, we investigated ING4 immunoexpression in gastrointestinal stromal tumors (GISTs) and its prognostic value. Method The expression of ING4 and Ki67 was investigated in 41 samples of various risk gastrointestinal stromal tumors by immunohistochemical technique. The associations of ING4 expression and clinicopathological parameters, and prognosis of the patients, were analyzed by multivariate Cox regression analysis. Results ING4 expression showed a decreased trend from lower-risk to high-risk gastrointestinal stromal tumors, and an opposite trend for Ki67 expression. In lower-risk tumors, it was found the expression level of ING4 was 78.95 % ± 27.90 % and that of Ki67 was 4.42 % ± 3.75 %. However, in high-risk tumors, the expression level of ING4 was 9.23 % ± 7.66 % and that of Ki67 was 18.50 % ± 9.09 %. There was a strongly negative correlation between the expression levels of ING4 and Ki67. A significant difference was observed in the expression of ING4 between invasion and non-invasion (p \ 0.001). The expression of ING4 was markedly correlated with tumor size (p \ 0.001), mitotic index (p \ 0.001), tumor necrosis (p = 0.021), invasion (p \ 0.001), recurrence and metastasis (p = 0.021), and mortality (p \ 0.001). Conclusion The low expression level of ING4 protein was correlated with high-risk GISTs. ING4 might be involved in the progression of GISTs and inhibit its invasion. ING4 might be one of the prognostic indicators in GISTs.

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Section: Discussionsupporting

confidence: 69%

Low ING4 protein expression detected by paraffin-section immunohistochemistry is associated with poor prognosis in untreated patients with gastrointestinal stromal tumors

et al. 2013

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“…We collected histoclinical and gene expression data of clinical GIST samples from our 2 databases 57,58 and 3 public data sets 53,59,60 from the National Center for Biotechnology Information (NCBI)/Genbank GEO and ArrayExpress databases. The 5 datasets are described in Table S5.…”

Section: Tumor Samplesmentioning

confidence: 99%

“…The 5 datasets are described in Table S5. Samples were profiled using whole-genome DNA microarrays: Affymetrix U133 Plus 2.0 [57][58][59] , and Agilent 44K. 53,60 The pooled data set contained 159 samples, including 139 with localized GIST treated with primary surgery without adjuvant imatinib.…”

Section: Tumor Samplesmentioning

confidence: 99%

PDL1 expression is an independent prognostic factor in localized GIST

et al. 2015

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Gastrointestinal stromal tumors (GIST) are the most frequently occurring digestive sarcomas. The prognosis of localized GIST is heterogeneous, notably for patients with an Armed Forces Institute of Pathology (AFIP) intermediate or high risk of relapse. Despite imatinib effectiveness, it is crucial to develop therapies able to overcome the resistance mechanisms. The immune system represents an attractive prognostic and therapeutic target. The Programmed cell Death 1 (PD1)/programmed cell death ligand 1 (PDL1) pathway is a key inhibitor of the immune response; recently, anti-PD1 and anti-PDL1 drugs showed very promising results in patients with solid tumors. However, PDL1 expression has never been studied in GIST. Our objective was to analyze PDL1 expression in a large series of clinical samples. We analyzed mRNA expression data of 139 operated imatinib-untreated localized GIST profiled using DNA microarrays and searched for correlations with histoclinical features including postoperative metastatic relapse. PDL1 expression was heterogeneous across tumors and was higher in AFIP low-risk than in high-risk samples, and in samples without than with metastatic relapse. PDL1 expression was associated with immunity-related parameters such as T-cell-specific and CD8C T-cell-specific gene expression signatures and probabilities of activation of interferon a (IFNa), IFNg, and tumor necrosis factor a (TNFa) pathways, suggesting positive correlation with a cytotoxic T-cell response. In multivariate analysis, the PDL1-low group was associated with a higher metastatic risk independently of the AFIP classification and the KIT mutational status. In conclusion, PDL1 expression refines the prediction of metastatic relapse in localized GIST and might improve our ability to better tailor adjuvant imatinib. In the metastatic setting, PDL1 expression might guide the use of PDL1 inhibitors, alone or associated with tyrosine kinase inhibitors.

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“…In recent years, there has been considerable interest in applying advanced proteomics technologies to the discovery of predictive biomarkers (12,13). We and others have successfully applied MALDI MS-based protein profiling techniques for predicting the efficacy of chemoradiotherapy and molecular targeting therapy (14,15).…”

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confidence: 99%

Survival Prediction for Pancreatic Cancer Patients Receiving Gemcitabine Treatment

Matsubara

Ono

Honda

et al. 2010

Molecular & Cellular Proteomics

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Although gemcitabine monotherapy is the standard treatment for advanced pancreatic cancer, patient outcome varies significantly, and a considerable number do not benefit adequately. We therefore searched for new biomarkers predictive of overall patient survival. Using LC-MS, we compared the base-line plasma proteome between 29 representative patients with advanced pancreatic cancer who died within 100 days and 31 patients who survived for more than 400 days after receiving at least two cycles of the same gemcitabine monotherapy. Identified biomarker candidates were then challenged in a larger cohort of 304 patients treated with the same protocol using reverse-phase protein microarray. Among a total of 45,277 peptide peaks, we identified 637 peaks whose intensities differed significantly between the two groups (p < 0.001, Welch's t test). Two MS peaks with the highest statistical significance (p ‫؍‬ 2.6 ؋ 10 ؊4 and p ‫؍‬ 5.0 ؋ 10 ؊4) were revealed to be derived from ␣ 1 -antitrypsin and ␣ 1 -antichymotrypsin, respectively. The levels of ␣ 1 -antitrypsin (p ‫؍‬ 8.9 ؋ 10 ؊8) and ␣ 1 -antichymotrypsin (p ‫؍‬ 0.001) were significantly correlated with the overall survival of the 304 patients. We selected ␣ 1 -antitrypsin (p ‫؍‬ 0.0001), leukocyte count (p ‫؍‬ 0.066), alkaline phosphatase (p ‫؍‬ 8.3 ؋ 10 ؊8 ), and performance status (p ‫؍‬ 0.003) using multivariate Cox regression analysis and constructed a scoring system (nomogram) that was able to identify a group of high risk patients having a short median survival time of 150 days (95% confidence interval, 123-187 days; p ‫؍‬ 2.0 ؋ 10 ؊15 , log rank test). The accuracy of this model for prognostication was internally validated and showed good calibration and discrimination with a bootstrap-corrected concordance index of 0.672. In conclusion, an increased level of ␣ 1 -antitrypsin is a biomarker that predicts short overall survival of patients with advanced pancreatic cancer receiving gemcitabine monotherapy. Although an external validation study will be necessary, the current model may be useful for identifying patients unsuitable for the standardized therapy. Molecular & Cellular Proteomics 9:695-704, 2010.

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Distinct Gene Expression–Defined Classes of Gastrointestinal Stromal Tumor

Cited by 113 publications

References 33 publications

Low ING4 protein expression detected by paraffin-section immunohistochemistry is associated with poor prognosis in untreated patients with gastrointestinal stromal tumors

Low ING4 protein expression detected by paraffin-section immunohistochemistry is associated with poor prognosis in untreated patients with gastrointestinal stromal tumors

PDL1 expression is an independent prognostic factor in localized GIST

Survival Prediction for Pancreatic Cancer Patients Receiving Gemcitabine Treatment

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