Gastroenterology

Gastroenterology

Volume 130, Issue 6, May 2006, Pages 1573-1581
Gastroenterology

Clinical–alimentary tract
Gastrointestinal Stromal Tumors With KIT Exon 11 Deletions Are Associated With Poor Prognosis

https://doi.org/10.1053/j.gastro.2006.01.043Get rights and content

Background & Aims: Gain-of-function mutations in the KIT receptor tyrosine kinase gene and rare mutations in the platelet-derived growth factor receptor α (PDGFRA) gene are important events in gastrointestinal stromal tumor (GIST) development. Different mutations are reportedly associated with distinctive phenotypes and possibly clinical behavior. We investigated the correlation among mutation type, phenotype, and clinical course in a preimatinib, population-based series of GIST with long-term follow-up. Methods: Genomic DNA from 177 GIST patients was analyzed for KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18 mutations using denaturating high-performance liquid chromatography and bidirectional sequencing. Results:KIT exon 11 mutations were detected in 101 of 177 GIST (61 deletions, 23 missense mutations, and 17 duplications); wild-type (WT) KIT and PDGFRA were detected in 63; KIT exon 9 and exon 17 mutations in 6 and 1, respectively; and PDGFRA exons 12 and 18 mutations in 3 each. GIST >5 cm vs GIST ≤1 cm had mutations in 73% and 33%, respectively. KIT exon 11 deletions were significantly associated with a higher proportion of high risk or overtly malignant groups compared with WT GIST. KIT exon 11 deletions adversely affected outcome. KIT exon 11 duplications and exon 9 mutations were found exclusively in gastric and small intestinal GIST, respectively. Conclusions: KIT exon 11 deletion is an independent adverse prognostic factor in patients with GIST.

Section snippets

Patient Series

All potential cases of GIST diagnosed and treated from 1983 through 2000 within Västra Götaland, a province in western Sweden with a population of 1.3–1.6 million, were retrieved and analyzed.29 Criteria for the diagnosis of GIST included tumor site (in or adjacent to the gastrointestinal tract, mesentery, omentum, or retroperitoneum), spindled and/or epithelioid morphology, and immunoreactivity for CD117. A total of 259 patients with clinically detected primary GIST were identified. Of these,

Patient Series, Tumor Characteristics, and Mutational Status

Data from 177 patients (1990–2000) regarding mutation status, tumor site and size, mitotic rate (per 50 high-power fields [hpf]), proliferative index (Ki67 max %), risk group according to the consensus report,34 GIST risk score (tumor size in cm) + proliferative index as Ki67 max %,29 recurrent tumor disease (local recurrence and/or metastasis), and survival are summarized in Table 1.

Mutation Analysis and Phenotypic and Prognostic Correlations

In the older material (1983–1989), a low frequency of mutations was detected, overall mutation rate 37.5% (WT,

Discussion

Numerous studies of GIST have demonstrated primarily gain-of-function mutations in the receptor tyrosine kinase genes KIT and rare mutations in PDGFRA. The vast majority of KIT gene mutations reportedly involve exon 11.4, 23, 35 However, studies regarding the frequency of exon 11 KIT mutations in GIST vary from 20% to 92%.35 This large variation could be attributed to referral center bias, analysis of fresh-frozen vs formalin-fixed and paraffin-embedded tissues, and methodologic aspects for

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      Finally, an in vitro experiment using GIST-T1 cell line indicated that the minimum number of cells required to amplify KIT gene from RNA was one tenth of that required to amplify it from DNA. Mutation analysis is useful not only for diagnosing GIST but also for predicting the effects of molecular targeting medicines and the risk of recurrence after surgery [4–10,19,20]. However, such analyses have been exclusively performed using DNA extracted from surgically resected samples.

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    Supported by the Swedish Cancer Society, Sahlgrenska Academy (the government ALF agreement), Inga-Britt and Arne Lundberg Research Foundation, Swedish Medical Research Foundation, Johan Jansson Foundation for Cancer Research, Assar Gabrielsson Research Foundation, Göteborg Medical Society, Capio Research Foundation, Björnsson Research Foundation, King Gustav V Jubilee Clinical Cancer Research Foundation, and Sahlgrenska University Hospital Research Foundation.

    1

    J.A. and P.B. contributed equally to this paper.

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