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Familial Gastrointestinal Stromal Tumors Caused by the Novel KIT Exon 17 Germline Mutation N822Y

Thalheimer, Andreas MD*; Schlemmer, Marcus MD; Bueter, Marco MD*; Merkelbach-Bruse, Sabine PhD; Schildhaus, Hans-Ulrich MD; Buettner, Reinhard MD, PhD; Hartung, Edgar MD§; Thiede, Arnulf MD, PhD*; Meyer, Detlef MD, PhD*; Fein, Martin MD, PhD*; Maroske, Jorn MD; Wardelmann, Eva MD, PhD

The American Journal of Surgical Pathology: October 2008 - Volume 32 - Issue 10 - p 1560-1565
doi: 10.1097/PAS.0b013e318172ce6f
Original Articles

Gastrointestinal stromal tumors (GISTs) are most often associated with oncogenic mutations of the KIT gene resulting in activation of the tyrosine kinase receptor KIT. Familial GIST syndrome based on a hereditary predisposition to develop GIST owing to a germline mutation is exceedingly rare. We describe a kindred with familial GIST displaying a novel germline mutation in exon 17. Three siblings (2 females, 1 male; 42 to 49 y) underwent surgery for multiple intra-abdominal tumors within a 3-year period. Their father had been operated on for gastric and jejunal tumors 20 years previously. The GIST was confirmed by immunohistochemistry in each sibling. Tumor and blood samples of the family members were analyzed for mutations in KIT and platelet-derived growth factor receptor (PDGFRα) genes. All examined lesions were of spindle cell type with expression of CD117. The tumor material exhibited a novel point mutation in codon 822 in exon 17 resulting in the replacement of asparagine by tyrosine (N822Y). The same mutation was detected in the father's blood sample. One healthy brother of the 3 siblings showed a wild-type sequence of the KIT gene. The germline mutation in exon 17 of the KIT gene identified in this kindred is very different from previously reported mutations of the KIT gene in familial GIST. Although the penetrance of KIT mutations is as yet unknown, assessment of the unaffected kindred of GIST patients for the presence of this mutation could help to distinguish individuals at high risk from those at virtually no risk.

*Department of Surgery, University of Wuerzburg, Wuerzburg

Department of Hematology and Oncology, University of Munich and GSF National Research Center for Environment and Health, Munich

Department of Pathology, University of Bonn Medical Center, Bonn

§Department of Medicine, Caritas-Hospital, Bad Mergentheim, Baden-Württemberg Land

Department of Surgery, Hospital Rothenburg, Tauber, Bavaria, Germany

No conflict of interest exists.

Identity of amplicon sequences confirmed by database search, accession no. HSU63834, NCBI database:

Andreas Thalheimer and Marcus Schlemmer contributed equally to this study.

Correspondence: Dr Andreas Thalheimer, MD, Department of Surgery, University of Wuerzburg, Oberduerrbacher Street 6, Wuerzburg 97080, Germany (e-mail:

© 2008 Lippincott Williams & Wilkins, Inc.