Gastrointestinal Stromal Tumors With KIT Exon 11 Deletions Are Associated With Poor Prognosis

Andersson, Jan-Erik; Bümming, Per; Meis‐Kindblom, Jeanne M.; Sihto, Harri; Nupponen, Nina N.; Joensuu, Heikki; Odén, Anders; Gustavsson, Bengt; Kindblom, Lars Gunnar; Nilsson, Bengt

doi:10.1053/j.gastro.2006.01.043

Cited by 207 publications

(167 citation statements)

References 30 publications

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“…3,39 In this study, we classified KIT genotype into aggressive genotype (KIT exon 11 deletion or KIT exon 9 duplication) and indolent genotype (KIT exon 11 missense mutation, KIT exon 11 internal tandem duplication or KIT wild). Interestingly, the fascin-1 mRNA level was significantly higher in GISTs with aggressive KIT genotype than in those with indolent KIT genotype (P ¼ 0.0455), although limited number of cases were examined.…”

Section: Discussionmentioning

confidence: 99%

Fascin-1 overexpression and miR-133b downregulation in the progression of gastrointestinal stromal tumor

2013

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MicroRNAs (miRNAs) are small, non-coding RNAs that are up-or downregulated in several types of cancer, and have an important role in the tumorigenesis and progression. To better understand the role of aberrantly expressed miRNAs and their target genes affecting the biology of gastrointestinal stromal tumor (GIST), we performed miRNA array in 19 cases of GIST, and found that several miRNAs, including miR-133b, were downregulated in high-grade GISTs. Subsequently, quantitative real-time reverse transcription-PCR revealed that fascin-1 mRNA was upregulated in accordance with miR-133b downregulation in high-grade GIST; this result was consistent with a previous report showing that fascin-1 might be a direct target of miR-133b. We then examined the fascin-1 protein expression by immunohistochemical staining in 147 cases of GIST, and found that fascin-1 overexpression was significantly correlated with shorter disease-free survival time and several aggressive pathological factors, including tumor size, mitotic counts, risk grade, blood vessel invasion and mucosal ulceration. Our results suggest that downregulation of miR-133b and overexpression of fascin-1 may have an important role in the progression of GIST, and that fascin-1 may be a useful biomarker to predict the aggressive behavior.

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Section: Discussionmentioning

confidence: 99%

Fascin-1 overexpression and miR-133b downregulation in the progression of gastrointestinal stromal tumor

2013

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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%

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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“…The deletions are associated with a shorter progression-free and overall survival in comparison with the other exon 11 mutations. [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.…”

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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Gastrointestinal Stromal Tumors With KIT Exon 11 Deletions Are Associated With Poor Prognosis

Cited by 207 publications

References 30 publications

Fascin-1 overexpression and miR-133b downregulation in the progression of gastrointestinal stromal tumor

Fascin-1 overexpression and miR-133b downregulation in the progression of gastrointestinal stromal tumor

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?

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