1. ¹Department of Soft Tissue Pathology, Armed Forces Institute of Pathology, Washington, DC, USA
2. ²Department of Molecular Biology, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warszawa, Poland
3. ³Department of Biology and Genetics, Medical University of Gdansk, Gdansk, Poland
4. ⁴Department of Gastroenterology, Medical Center for Postgraduate Education, Warsaw, Poland
5. ⁵Department of Pathology, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warszawa, Poland
6. ⁶Department of Soft Tissue/Bone Sarcoma and Melanoma, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warszawa, Poland
7. ⁷Department of Pathology, Haartman Institute of the University of Helsinki, Helsinki, Finland
8. ⁸Department of Pathology, University Hospital Northern Norway, Tromso, Norway
9. ⁹Department of Pathology, Otto-von-Guericke University, Magdeburg, Germany
10. ¹⁰Department of Pathology, Collegium Medicum of the Jagiellonian University, Krakow, Poland
11. ¹¹Department of Pathology, Pomaranian Medical University, Szczecin, Poland
12. ¹²Department of Pathology, University College Hospital, Ibadan, Nigeria

Correspondence: Dr J Lasota, MD, Department of Soft Tissue and Orthopedic Pathology, Armed Forces Institute of Pathology, Building 54, 6825 16th Street, N.W., Washington, DC 20306-6000, USA. E-mail: lasota@afip.osd.mil

Received 11 April 2007; Revised 23 May 2007; Accepted 28 May 2007; Published online 16 July 2007.

Abstract

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of gastrointestinal tract. GISTs range from benign indolent neoplasms to highly malignant sarcomas. Gain-of-function mutations of tyrosine kinase receptors, KIT or PDGFRA, have been identified in most GISTs. In this study, we report 36 GIST patients whose tumors had homozygous KIT exon 11 mutations detected by direct sequencing of PCR products. Loss of heterozygosity in KIT locus and other chromosome 4 loci were documented in majority of these tumors. However, fluorescence in situ hybridization with KIT locus-specific probe and chromosome 4 centromeric enumeration probe showed no evidence of KIT hemizygosity in a majority of analyzed cases. These findings are consistent with duplication of chromosome 4 with KIT mutant allele. Homozygous KIT exon 11 mutations were found in 33 primary tumors and 7 metastatic lesions. In two cases, shift from heterozygosity to homozygosity was documented during tumor progression being present in metastases, but not in primary tumors. Among primary GISTs, there were 16 gastric, 18 intestinal and 2 from unknown locations. An average primary tumor size was 12 cm and average mitotic activity 32/50 HPFs. Out of 32 tumors 29 (90.6%) with complete clinicopathologic data were diagnosed as sarcomas with more than 50% risk of metastatic disease, and 26 of 29 patients with follow-up had metastases or died of disease. An average survival time among pre-imatinib patients, who died of the disease was 33.4 months. Based on these findings, we conclude that presence of homozygous KIT exon 11 mutations is associated with malignant course of disease and should be considered an adverse prognostic marker in GISTs.