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Tyrosine-kinase mutations in c-KIT and PDGFR-alpha genes of imatinib naïve adult patients with gastrointestinal stromal tumours (GISTs) of the stomach and small intestine: relation to tumour-biological risk-profile and long-term outcome

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Abstract

Background

The identification of activating mutations in either c-KIT cell surface growth factor receptor or platelet-derived growth factor receptor alpha (PDGFRA) has lead the way for the development of novel agents that selectively inhibit key molecular events in gastrointestinal stromal tumour (GIST) pathogenesis. The aim of this study was to investigate the role of c-KIT and PDGFRA gene mutations in primary resectable, imatinib naïve GISTs located in the stomach and small intestine.

Methods

All adult patients with GIST located in either stomach or small intestine who underwent surgical resection without prior imatinib (Glivec) treatment were included. DNA extraction and mutational analysis were performed. Mutational analyses were performed for c-KIT (exons 9, 11, 13, and 17) and the PDGFRA genes (exons 12, 14 and 18). Clinical and pathological parameters were analyzed in relation to the mutations in c-KIT and PDGFRA.

Results

A total of 38 patients who underwent surgery for GIST located in either the stomach (n = 24) or in the small intestines (n = 14) were included. Mutations were found in 31 of 38 (81.6 %) patients, with 24 (63.2 %) located in c-KIT and 7 (18.4 %) in the PDGRFA exons, respectively. Seven patients (18.4 %) were wildtype (WT). The most common mutation was in c-KIT exon 11. Incidentally found GISTs were significantly smaller (size >5 cm in 15 % for incidental vs. 71 % for symptomatic; OR of 13.4, 95 % CI 2.3–76.5; P = 0.001) and had lower mitotic rate (0 % for incidental vs. 44 % of the symptomatic; OR 0.52, 95 % CI 0.36–0.75; P = 0.005). Accordingly, the Fletcher grade was significantly better for incidental cases, with most having very low or low risk (85 %) in contrast to 19 of 25 (76 %) symptomatic cases showing moderate to high-risk features (OR 17.4, 95 % CI 2.98–101.7; P < 0.001). However, the distribution of c-KIT, PDGFRA and WT was not differently distributed between incidental and symptomatic GISTs. Long-term survival up to 25 years (median: 8 years) was best determined by Fletcher risk-score in the multivariate model (HR 14.1, 95 % CI 1.7–114.5; p = 0.013).

Conclusions

Long-term survival in resected GISTs of the stomach and small intestine is best determined by Fletcher risk-score. Mitotic activity appears related to tumour size and young age at onset. Mutational status did not influence the clinical or tumour-specific features in this cohort.

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Abbreviations

GIST:

Gastrointestinal stromal tumour

PDGFR-alpha:

Platelet-derived growth factor receptor

HES:

Haematoxylin, eosin, safran staining

WT:

Wild type

PCR:

Polymerase chain reaction

HPF:

High power field

HR:

Hazard ratio

95 % CI:

95 % Confidence interval

IHC:

Immunohistochemistry

ICC:

Interstitial cells of Cajal

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Authors and Affiliations

  1. Department of Surgery, Stavanger University Hospital, PO Box 8100, 4068, Stavanger, Norway

    Kjetil Søreide, Oddvar M. Sandvik & Jon Arne Søreide

  2. Department of Surgical Sciences, University of Bergen, Bergen, Norway

    Kjetil Søreide & Jon Arne Søreide

  3. Department of Pathology, Stavanger University Hospital, Stavanger, Norway

    Einar Gudlaugsson

  4. Department of Pathology, The Gade Institute, Haukeland University Hospital, Bergen, Norway

    Kjersti Mangseth & Hans Kristian Haugland

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  1. Kjetil Søreide
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Correspondence to Kjetil Søreide.

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Søreide, K., Sandvik, O.M., Søreide, J.A. et al. Tyrosine-kinase mutations in c-KIT and PDGFR-alpha genes of imatinib naïve adult patients with gastrointestinal stromal tumours (GISTs) of the stomach and small intestine: relation to tumour-biological risk-profile and long-term outcome. Clin Transl Oncol 14, 619–629 (2012). https://doi.org/10.1007/s12094-012-0851-x

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  • DOI: https://doi.org/10.1007/s12094-012-0851-x

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