Deletions Affecting Codons 557-558 of the <i>c</i>-<i>KIT</i> Gene Indicate a Poor Prognosis in Patients With Completely Resected Gastrointestinal Stromal Tumors: A Study by the Spanish Group for Sarcoma Research (GEIS)

Martín, Javier; Poveda, Andrés; Llombart‐Bosch, Antonio; Ramos, Rafael; Löpez‐Guerrero, José Antonio; Muro, Javier García del; Maurel, Joan; Calabuig, Silvia; Gutiérrez, Antonio; Sande, José L. González de; Martínez, Javier; Juan, Ana De; Laínez, Núria; Losa, Ferrán; Alija, V.; Escudero, P.; Casado, Antonio; García, Pilar; Blanco, Remei; Buesa, J. M.

doi:10.1200/jco.2005.19.554

Cited by 333 publications

(268 citation statements)

References 26 publications

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“…Initially it is proposed that the presence of genetic mutations could be used as a marker to predict malignancy or poor prognosis. [38][39][40][41][42][43] Since approximately 90% of the GISTs contain either KIT or PDGFRA gene mutations, it is apparently not a reliable criterion. 44 Studies indicated that the type of mutation may predict prognosis.…”

Section: Discussionmentioning

confidence: 99%

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Stage and histological grade of gastrointestinal stromal tumors based on a new approach are strongly associated with clinical behaviors

Hou

Zhou

et al. 2009

Modern Pathology

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Tumor stage and grade for gastrointestinal stromal tumors are poorly defined. To develop a better evaluation system, we assessed 12 clinical and pathological parameters in 613 patients with follow-up information. These parameters were classified into two gross spread parameters including liver metastasis and peritoneal dissemination, five microscopic spread parameters including lymph node metastasis, vascular, fat, nerve and mucosal infiltration, and five histological parameters including mitotic count Z10 per 50 high-power fields, muscularis propria infiltration, coagulative necrosis, perivascular pattern and severe nuclear atypia. The 5-year disease-free survival and overall survival of 293 patients without any of these predictive parameters of malignancy were 99% and 100%, respectively. They were regarded as nonmalignant and further evaluations on the stage and grade of these tumors were not performed. At least one and at most seven predictive parameters of malignancy were identified in 320 patients. For these patients, the 5-year disease-free survival and overall survival rates were 44% (mean 6.7 years) and 60% (mean 9.3 years), respectively. The disease-free survival showed significant difference between patients with and without gross spread (Po0.0001), with and without microscopic spread (P ¼ 0.0009). Disease-free survival and overall survival were associated with the number of predictive parameters of malignancy in patients without gross spread (Po0.0001 for both disease-free survival and overall survival), but not in patients with gross spread (P ¼ 0.882 and 0.441, respectively). Malignant gastrointestinal stromal tumors could be divided into clinical stage I and II based on the absence and presence of gross spread, respectively. The degree of malignancy of patients in clinical stage I could be graded according to the number of predictive parameters of malignancy. Patients in clinical stage II were of the highest degree of malignancy regardless of the number of parameters. We found that the clinical stage and grade were strongly associated with prognosis.

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Section: Discussionmentioning

confidence: 99%

“…44 Studies indicated that the type of mutation may predict prognosis. 40,41,[45][46][47] On the basis of our unpublished data and recent reports, the most reliable mutation type with independent prognostic role was homogenous deletion in exon 11 of KIT gene. 48 However, the frequency of this homogenous mutation is rare.…”

Section: Discussionmentioning

confidence: 99%

Stage and histological grade of gastrointestinal stromal tumors based on a new approach are strongly associated with clinical behaviors

Hou

Zhou

et al. 2009

Modern Pathology

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“…[12][13][14][15][16][17][18] In particular, deletions involving codons 557 and/or 558 are associated with malignant behavior. [19][20][21] Aside from exon 11 mutations, between 7 and 10% of GISTs have a mutation in an extracellular domain encoded by exon 9. 22 These mutations are thought to mimic the conformational change that the extracellular KIT receptor undergoes when ligand is bound.…”

Section: Kitmentioning

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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“…6 Although GISTs exhibit a spectrum of biologic behavior from benign to malignant, the molecular mechanism of tumor progression has not been fully clarified. Previous studies have reported the prognostic significance of tumor size, mitotic counts, tumor grade, Ki-67 labeling index (LI), 7 KIT mutation type, 4,8,9 p16 inactivation 10 and overexpression of cell-cycle regulators such as cyclin A, cyclin B1 and cdc2. 11 Angiogenesis is one of the key steps in the growth and metastasis of solid tumors.…”

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confidence: 99%

Prognostic significance of angiogenesis in gastrointestinal stromal tumor

et al. 2007

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Angiogenesis is important in the growth and metastasis of various kinds of solid tumors. To investigate the potential role of angiogenesis in gastrointestinal stromal tumor (GIST), an immunohistochemical analysis was performed in 95 cases of GISTs for microvessel density (MVD) and vascular endothelial growth factor (VEGF) expression. MVD was evaluated with immunohistochemical staining for CD31. A high level of MVD was significantly correlated with overexpression of VEGF, tumor location (intestine4stomach), tumor size (Z5 cm), tumor grade (high4intermediate4low grade) (P ¼ o0.0001, 0.0422, 0.0006, 0.0359, respectively). Of the 70 GISTs analyzed, KIT exon 11 mutations were detected in 45 cases (64.3%) and KIT exon 9 mutations in two cases (2.9%). No mutations were found in KIT exons 13 and 17, and platelet-derived growth factor receptor-alpha exons 12 and 18. Interestingly, VEGF expression level was significantly higher in the non-KIT exon 11 mutant group than in the KIT exon 11 mutant group (P ¼ 0.0266). In univariate analysis, tumor grade (high grade), tumor size (Z5 cm), mitotic count (Z5/50 high-power fields), Ki-67 labeling index (Z4.6%), MVD (Z7.0/0.95 mm 2 ) and VEGF expression (high) were significantly associated with a shorter period of disease-free survival (P ¼ o0.0001, 0.0199, 0.0055 0.0027, 0.0028 and 0.0302, respectively). In multivariate analysis, tumor grade and MVD were identified as independent worse prognostic factors (P ¼ 0.0007, 0.0152, respectively). In conclusion, our results suggest that the evaluation of MVD and VEGF expression is useful for predicting the aggressive biologic behavior of GIST, and that angiogenesis associated with VEGF may play an important role, at least in part, in the progression of GIST. Modern Pathology (2007) 20, 529-537.

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Deletions Affecting Codons 557-558 of the c-KIT Gene Indicate a Poor Prognosis in Patients With Completely Resected Gastrointestinal Stromal Tumors: A Study by the Spanish Group for Sarcoma Research (GEIS)

Abstract: Deletions affecting codons 557 to 558 are relevant for the prognosis of RFS in GIST patients. This critical genetic alteration should be considered to be a new prognostic stratification variable for randomized trials exploring imatinib mesylate in the adjuvant setting in GIST patients.

Cited by 333 publications

References 26 publications

Stage and histological grade of gastrointestinal stromal tumors based on a new approach are strongly associated with clinical behaviors

Stage and histological grade of gastrointestinal stromal tumors based on a new approach are strongly associated with clinical behaviors

Gastrointestinal stromal tumors: what do we know now?

Prognostic significance of angiogenesis in gastrointestinal stromal tumor

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