Allelic Loss of 14q and 22q, <i>NF2</i> Mutation, and Genetic Instability Occur Independently of c‐<i>kit</i> Mutation in Gastrointestinal Stromal Tumor

Fukasawa, Tomoki; Chong, Ja-Mun; Sakurai, Shunsuke; Koshiishi, Naoki; Ikeno, Rie; Tanaka, Akira; Matsumoto, Yoshirô; Hayashi, Yukiko; Koike, Masato; Fukayama, Masashi

doi:10.1111/j.1349-7006.2000.tb00910.x

Cited by 72 publications

(74 citation statements)

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“…53,79,84 Chromosomal and Molecular Alterations During GIST Progression of GISTs demonstrate either monosomy of chromosome 14, or partial loss of 14q. 37,[85][86][87][88][89] Interestingly, these chromosome 14 abnormalities are observed in both KIT-mutant and PDGFRA-mutant GISTs. 37,43 Deletions of 14q11.2 include the genes PARP2, APEX1, and NDRG2, whereas deletions of 14q32 include the SIVA gene.…”

Section: Micro-gistsmentioning

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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Section: Micro-gistsmentioning

confidence: 99%

Gastrointestinal stromal tumors: what do we know now?

2014

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“…In some tumors, both types of alterations may coexist. It is now widely accepted that, in GISTs, DNA alterations play a major role in pathogenesis and disease progression (6). Recently, molecular resistance mechanisms of GIST toward imatinib (Gleevec, Novartis, Basel, Switzerland) therapy are being described.…”

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confidence: 99%

Microsatellite DNA Alterations of Gastrointestinal Stromal Tumors Are Predictive for Outcome

Schurr¹,

Wolter²,

Kaifi³

et al. 2006

Clinical Cancer Research

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Purpose: In gastrointestinal stromal tumors (GIST), loss of heterozygosity (LOH) on chromosome 22 and its presumptive biological function has been described. The prognostic value of these and other DNA regions for patient survival remains unclear. Experimental Design: Sixty patients who underwent surgery at our institution between 1992 and 2003 for GIST were histopathologically reclassified by immunohistochemistry and the GIST consensus group criteria 2001. Twenty-one microsatellite loci on chromosomes 3, 9, 13, 17, 18, and 22 were screened for alterations in tumor and healthy DNA. Survival was calculated by Kaplan-Meier plots. Results: Eleven (18.3%) of 60 patients showed metastases at presentation. Thirteen (21.7%) of 60 were high-risk GISTs. LOH was found in all tumors. Twenty-eight (46.7%) of 60 showed more than two LOH in 21 microsatellite marker sites. The frequency of single marker LOH varied from 1.7% to 28.3% among tumors. Frequent LOH was found on chromosomes 22 and 17. The correlation of LOH positivity and the consensus scoring was significant (P = 0.005, m 2 test). After a median observation time of 33.3 months (95% confidence interval, 23.9-42.6), overall survival was best for patients with tumors of very low, low, and intermediate risks with only 6 of 36 death events, whereas 14 of 24 high-risk and metastasized patients had died (P < 0.001, log-rank test).Likewise, LOH significantly predicted survival (P = 0.013) and the effect was particularly detrimental for LOH on chromosome 17 (P < 0.001).Conclusions: LOH is a useful phenomenon for the prognosis of GIST. Rather than chromosome 22 markers, chromosome 17 markers independently predict survival.

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“…NF2 encodes a 595-amino-acid protein, schwannomin or merlin (moesin-ezrin-radixin-likeprotein), which exhibits significant homology to a highly conserved family of proteins involved in connecting the cytoskelton to components of plasma membranes. NF2 is considered to be a tumor suppressor gene for tumors associated with NF2 disorders (schwannoma and meningioma) and for NF2-unrelated tumors (mesothelioma, colon cancer, and gastrointestinal stromal tumor) [6][7][8].…”

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confidence: 99%