1. ¹Molecular Oncology Program, Molecular Oncology and Aging Group, Vall d'Hebron Hospital Research Institute, Passeig Vall d'Hebron, Barcelona, Spain
2. ²Functional Genomics Program, Molecular Oncology and Aging Group, Molecular Biology and Biochemistry Research Center (CIBBIM), Vall d'Hebron Hospital Research Institute, Passeig Vall d'Hebron, Barcelona, Spain
3. ³Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
4. ⁴Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
5. ⁵Endometrial Cancer Study Group, Cancer Research Institute of The Canary Islands (ICIC), Canary Islands, Spain
6. ⁶Department of Biochemistry and Physiology, Faculty of Health Sciences, University of Las Palmas de Gran Canaria, Las Palmas de GC, Canary Islands, Spain
7. ⁷Institute of pathology, Technical University of Munich, Munich, Germany
8. ⁸Department of Obstetrics and Gynecology, Hospital Universitario Materno-Infantil de Canarias, Las Palmas de GC, Canary Islands, Spain
9. ⁹Dr Falcón Gynecologycal Institute, Las Palmas de GC, Canary Islands, Spain
10. ¹⁰Department of Pathology, Hospital Universitario Materno-Infantil de Canarias, Las Palmas de GC, Canary Islands, Spain
11. ¹¹Institute of Pathology, Mannheim, Germany
12. ¹²Program of Cytogenetics and Epigenetics, Molecular Genetics and Aging Group, Molecular Biology and Biochemistry Research Center (CIBBIM), Vall d'Hebron Hospital Research Institute, Passeig Vall d'Hebron, Barcelona, Spain
13. ¹³Burnham Institute for Medical Research, La Jolla, CA, USA
14. ¹⁴First Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan
15. ¹⁵Department of Applied Tumor Biology (ATB), Institute of Pathology, Im Neuenheimer Feld 220/221, Heidelberg, Germany

Correspondence: Dr D Arango, Functional Genomics Program, Molecular Oncology and Aging Group, Molecular Biology and Biochemistry Research Center (CIBBIM), Valle Hebron Hospital Research Institute, Passeig Vall d'Hebron 119-129, Barcelona 08035, Spain. E-mail: darango@ir.vhebron.net

¹⁶These authors contributed equally for this work.

Received 7 April 2006; Revised 24 May 2006; Accepted 24 May 2006; Published online 3 July 2006.

Abstract

The EPH/EFN family of receptor tyrosine kinases regulates cell adhesion and migration and has an important role in controlling cell positioning in the normal intestinal epithelium. Inactivation of EPHB2 has recently been shown to accelerate tumorigenesis in the colon and rectum, and we have previously demonstrated frequent frameshift mutations (41%) in an A9 coding microsatellite repeat in exon 17 of EPHB2 in colorectal tumors with microsatellite instability (MSI). In this study, we extended these analyses to extracolonic MSI cancers, and found frameshift EPHB2 mutations in 39% (25/64) of gastric tumors and 14% (8/56) of endometrial tumors. Regression analysis of these EPHB2 mutation data on the basis of our previously proposed statistical model identified EPHB2 as a selective target of frameshift mutations in MSI gastric cancers but not in MSI endometrial carcinomas. These results suggest a functional role for EPHB2 in gastric tumor progression, and emphasize the differences between the tumorigenic processes in MSI gastrointestinal and endometrial cancer.