Molecular targets for tumour progression in gastrointestinal stromal tumours - PubMed (original) (raw)

doi: 10.1136/gut.2003.021238.

R Schneider-Stock, M Sarlomo-Rikala, J Lasota, M Smolkin, G Petroni, A Zaika, C Boltze, F Meyer, L Andersson, S Knuutila, M Miettinen, W El-Rifai

Affiliations

Molecular targets for tumour progression in gastrointestinal stromal tumours

N Koon et al. Gut. 2004 Feb.

Abstract

Background and aims: The distinction between benign and malignant gastrointestinal stromal tumours (GISTs) is often unclear at the clinical and histopathology levels. GISTs are believed to arise from the stem cells of Cajal. In order to define genetic biomarkers and identify target genes related to GIST progression, we analysed and compared benign and malignant GISTs with verified follow up data using cDNA expression arrays.

Methods: Eight genes were frequently overexpressed in malignant GISTs and their overexpression was confirmed using quantitative real time reverse transcription-polymerase chain reaction. These genes included ezrin (villin 2 (VIL2)), collagen 8 alpha 1 subunit (COL8A1), G2/mitotic specific cyclin B1 (CCNB1), high mobility group protein (HMG2), TSG101 tumour susceptibility protein, CENP-F kinetochore protein, protein tyrosine kinase 2 (FAK), and protein kinase DYRK2. To test these genes in a clinical setting, we obtained diagnostic samples of 16 additional GISTs that were classified at diagnosis as benign, malignant, and uncertain malignant potential (UMP).

Results: There was remarkable gene overexpression in all malignant GISTs. Statistical analyses revealed significant correlations between overexpression of several gene pairs in malignant GISTs. We found the strongest correlations (rho>0.70) among the significant correlations (p<0.01) between CCNB1-CENP-F (rho = 0.87) and CCNB1-FAK (rho = 0.73). Gene expression of the UMP GISTs suggested two different groups. Three UMP GISTs had gene expression consistent with malignant tumours and their follow up data revealed that indeed these patients had recurrences later on. On the other hand, UMP GISTs that had low gene expression levels continued free of disease for several years.

Conclusions: These results provide insight into the oncogenesis of GISTs and suggest that testing the expression profile of a number of genes may segregate GISTs into groups of different tumour behaviour.

PubMed Disclaimer

Figures

Figure 1

Figure 1

Visual demonstration of expression intensities in malignant gastrointestinal stromal tumours (GIST Nos 4–9) compared with benign GISTs using Treeview software (Michael Eisen, Stanford University, California, USA). Twenty seven genes were overexpressed in one or more malignant GISTs compared with the average of benign GISTs (GIST Nos 1–3). Expression intensity correlates with the brightness of the red colour.

Figure 2

Figure 2

Quantitative real time reverse transcription-polymerase chain reaction (RT-PCR) analyses of eight genes (VIL2, villin 2; COL8, collagen 8 alpha 1 subunit; CCNB1, G2/mitotic specific cyclin B1; HMG2, high mobility group protein; TSG, TSG101 tumour susceptibility protein; CENP-F, CENP-F kinetochore protein; FAK, protein tyrosine kinase 2; and DYRK2, protein kinase DYRK2) in gastrointestinal stromal tumour (GIST) Nos 10–25. Malignant and uncertain malignant potential (UMP) GISTs were compared with benign GISTs (GIST Nos 21–24) to obtain overexpression folds. Gene overexpression was considered significant at a ratio of ⩾5.0. The overexpression fold was calculated as described previously. *COL8 and *DYRK2 were not statistically significant, as shown in table 3 ▶. Sample numbers are shown on the x axis; overexpression folds are shown on the y axis. †Primary diagnosis was UMP GIST, patients had no recurrence on follow up. ‡Primary diagnosis was UMP GIST, patients developed recurrences on follow up. §Primary diagnosis was benign, patients died after one month of renal failure.

References

    1. Sarlomo-Rikala M, El-Rifai W, Lahtinen T, et al. Different patterns of DNA copy number changes in gastrointestinal stromal tumors, leiomyomas, and schwannomas. Hum Pathol 1998;29:476–81. - PubMed
    1. El-Rifai W, Sarlomo-Rikala M, Andersson LC, et al. DNA sequence copy number changes in gastrointestinal stromal tumors: tumor progression and prognostic significance. Cancer Res 2000;60:3899–903. - PubMed
    1. Miettinen M, Lasota J. Gastrointestinal stromal tumors—definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis. Virchows Arch 2001;438:1–12. - PubMed
    1. Miettinen M, El-Rifai W, Lasota J, et al. Evaluation of malignancy and prognosis of gastrointestinal stromal tumors: a review. Hum Pathol 2002;33:478–83. - PubMed
    1. Rubin BP, Singer S, Tsao C, et al. KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer Res 2001;61:8118–21. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources