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Familial gastrointestinal stromal tumours with germline mutation of the KIT gene

Nature Genetics volume 19, pages 323–324 (1998)Cite this article

Gastrointestinal stromal tumour (GIST) is the most common mesenchymal tumour of the human gastrointestinal tract. Most GISTs are solitary, and gain-of-function mutations of the KIT protooncogene have been found in these tumours1. We report here a family with multiple GISTs: affected members all have a KIT mutation occurring between the transmembrane and tyrosine kinase domains, which is also the region where mutations have been found in solitary GISTs (ref. 1). The KIT mutation in this family was detected not only in tumours but also in leukocytes, indicating that GISTs constitute a familial cancer syndrome2.

The benign GISTs obtained from cases 5, 9 and 10, and the malignant GIST from case 9, all expressed the KIT protein (Fig. 1b– e). DNA was extracted from paraffin-embedded specimens of the tumours3, and the mutation was investigated using single-strand conformation polymorphism analysis4 (SSCP). SSCP of tumours from cases 5 and 10 showed wild-type and mutant bands at exon 11 (Fig. 1 f). Direct sequencing of the mutant bands of exon 11 showed deletion of one of two consecutive valine residues (codon 559 and 560, GTTGTT) which are located between the transmembrane and tyrosine kinase domains. Unfortunately, DNA samples suitable for SSCP and direct sequencing were not obtained from tumours of case 9. Next, we obtained DNA from peripheral leukocytes of cases 5 and 10 and their family members. The valine deletion was detected in leukocyte DNA from cases 5, 10 and 15, but not in DNA from other family members. Case 15 is 22 years old and has so far had no abdominal symptoms.

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Figure 1: A family with multiple GISTs and mutation of the KIT gene.
Figure 2: Constitutive activation of mutant KIT and autonomous proliferation of its transfectant.

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Acknowledgements

We thank the family members for their cooperation in this study. Supported by grants from the Japanese Ministry of Education, Science, Culture and Sports, and the Ministry of Health and Welfare.

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Authors and Affiliations

  1. Department of Surgery I, Osaka University Medical School, Yamada-oka, 2-2, Japan

    Toshirou Nishida, Masahiko Taniguchi & Hikaru Matsuda

  2. Department of Pathology, Osaka University Medical School, Yamada-oka, 2-2, Japan

    Seiichi Hirota, Koji Hashimoto, Harumi Nakamura & Yukihiko Kitamura

  3. Department of Internal Medicine II Osaka University Medical School, Yamada-oka, 2-2, Japan

    Koji Isozaki

  4. Department of Hematology/Oncology, Osaka University Medical School, Yamada-oka, 2-2, Japan

    Yuzuru Kanakura

  5. Division of Pathology, Kinan General Hospital, Tanabe, Japan

    Tomoyuki Tanaka

  6. Department of Surgery, Kitano Hospital, Osaka, Japan

    Arimichi Takabayashi

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  1. Toshirou Nishida
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Correspondence to Toshirou Nishida.

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Nishida, T., Hirota, S., Taniguchi, M. et al. Familial gastrointestinal stromal tumours with germline mutation of the KIT gene. Nat Genet 19, 323–324 (1998). https://doi.org/10.1038/1209

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