Elsevier

Human Pathology

Volume 34, Issue 9, September 2003, Pages 872-879
Human Pathology

Chromosome 22q alterations and expression of the NF2 gene product, merlin, in gastrointestinal stromal tumors

https://doi.org/10.1016/S0046-8177(03)00349-6Get rights and content

Abstract

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract. A characteristic genetic alteration in GISTs is constitutive activation of the c-kit proto-oncogene, but alterations in chromosomes 14 and 22 may also play a role in the molecular pathogenesis. In this study, 42 GISTs were analyzed for loss of heterozygosity (LOH) on the long arm of chromosome 22 (22q). Overall, 69% of the tumors studied showed LOH with at least 1 of the 22q markers. Allele losses were compared with tumor mitotic activity, the most commonly used prognostic marker for this tumor. Interestingly, allele deletion at 22q was significantly more frequent in tumors with high mitotic activity (≥l2 mitoses/10 high-power fields [HPF]) than in tumors with low mitotic activity (<2 mitoses/HPF)—88% versus 56% (P < 0.01). A total of 26% (11 of 42) of all tumors demonstrated loss of all 22q sites analyzed, consistent with the loss of 1 copy of the entire long arm. Such tumors carried a 4.6-fold (95% confidence interval, 0.5 to 49.8) risk for recurrence compared with tumors with no LOH. LOH was frequently detected at the neurofibromatosis 2 (NF2) tumor-suppressor gene locus at 22q12. Sequencing of the NF2 gene from 5 GISTs did not reveal mutations, however. Furthermore, 16 of 19 tumors (84%) analyzed by immunohistochemistry were positive for the NF2 gene product, merlin. The findings suggest that allelic losses at 22q are associated with high mitotic activity and recurring disease, and that alterations in the NF2 gene are unlikely to participate in the pathogenesis of GIST.

Section snippets

Tumor specimens

A total of 42 GISTs were collected from the files of the Department of Pathology, Haartman Institute, University of Helsinki (Table 1). Matching normal tissue samples were available from 29 patients. The study included 26 male and 16 female patients, with a median age of 64 years at the time of diagnosis (range, 41 to 87 years). Thirty-one tumors were located in the stomach, 10 tumors were in the small intestine (9 in the jejunum and 1 in the ileum), and 1 tumor was in the rectum. Tumor

Results

Tumor material consisted of 42 GISTs, the demographic data and clinical features of which are given in Table 1. Twelve highly polymorphic microsatellite markers that span the long arm of chromosome 22 and 2 complementary techniques were used for detection of LOH (Fig 2). Overall, 69% of the tumors showed LOH with at least 1 of the 22q markers. Allele losses were compared with tumor mitotic activity, the most commonly used prognostic marker for this tumor type. Of the 42 tumors, 17 (40%) showed

Discussion

This study has demonstrated that LOH at 22q is a frequent event in GISTs, with an overall frequency close to 70%. In GISTs with high mitotic activity, an indicator of potential malignancy, allelic losses occurred in nearly 90% of the tumors, whereas approximately half of the tumors with low mitotic activity exhibited LOH. A 4.6-fold risk of recurrence or disease-related death was observed in cases with 22q LOH at all informative sites as compared with those with no LOH. These data suggest the

Acknowledgements

The authors thank Tuula Niilola and Tuula Suitiala for skillful technical assistance and Dr. Timo Partanen and Anneli Ojajärvi for their expert statistical analyses.

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      The selection of the markers was based on the latest literature and our last studies [12, 14]. Hence, five markers on chromosome 22 were derived from a study on 42 GISTs, which associated the pathogenesis of GIST with the neurofibromatosis gene NF2 [10]. The other markers showed LOH in relevant regions in different carcinoma and sarcoma studies.

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    Supported by grants from The Finnish Cancer Organization, Helsinki University Central Hospital, The Sigrid Juselius Foundation, Luise and Henrik Kuningas Foundation, and the Academy of Finland.

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