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A somatic activating KRAS variant identified in an affected lesion of a patient with Gorham–Stout disease

Journal of Human Genetics volume 65, pages 995–1001 (2020)Cite this article

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Abstract

Gorham–Stout disease (GSD), a rare disorder of unknown etiology, is characterized by massive osteolysis that is associated with proliferation and dilation of lymphatic vessels. Variants in cancer-associated genes have been described in complex lymphatic anomalies. To explore the pathogenesis of GSD, we performed the amplicon-based deep sequencing on 50 cancer-related genes to assay affected tissues from the six patients with GSD. In one patient, a somatic activating KRAS c.182A > G variant (p.Q61R) was detected in 1% of the tissue sample. Conversely, the mutant allele was not detected in uninvolved normal skin and blood samples. Histopathology of the patient’s tissue sample showed proliferation of abnormal lymphatic and blood vascular endothelial cells, osteoclasts, and activated macrophages. The activating KRAS variant is a known ‘hotspot’ variant, frequently identified in several types of human cancer. This is the first report of identifying a pathogenic variant in a patient with GSD. This finding may set the stage for elucidation of pathophysiology and the development of novel therapies for GSD.

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Acknowledgements

We thank Dr. Saori Endo, Dr. Shiho Yasue, Dr. Akihito Nagano, and Dr. Toshiyuki Fukao of Gifu University, Dr. Yasuyuki Shibuya of Nagoya City University Hospital, Dr. Koji Yokoyama of Japanese Red Cross Wakayama Medical Center, Dr. Masataka Takahashi of the University of Tokyo Hospital, and Dr. Mitsuharu Fukazawa of Tagawa Municipal Hospital for their cooperation in the data analyses. We thank Dr. Koki Nagai, Dr. Taiki Abe, Ms. Yoko Tateda in Tohoku University for providing technical assistance of NGS analysis. We also acknowledge the technical support of the Biomedical Research Core of Tohoku University Graduate School of Medicine. We would like to thank Editage (www.editage.com) for English language editing.

Funding

The present study was supported partly by the Clinical Research-Clinical Trial Promotion Research Project (18lk0201055h0003), Practical Research Project for Rare/Intractable Diseases (18ek0109277h0002 and 18ek0109278h0002) from Japan’s Agency for Medical Research and Development (AMED), and a research grant from the Naito Foundation.

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Authors and Affiliations

  1. Department of Medical Genetics, Tohoku University School of Medicine, Sendai, 980-8574, Japan

    Akifumi Nozawa, Tetsuya Niihori & Yoko Aoki

  2. Department of Pediatrics, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, 501-1194, Japan

    Akifumi Nozawa & Michio Ozeki

  3. Department of Pathology, Gifu University Hospital, 1-1 Yanagido, Gifu, 501-1194, Japan

    Natsuko Suzui & Tatsuhiko Miyazaki

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  1. Akifumi Nozawa
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  2. Michio Ozeki
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  3. Tetsuya Niihori
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  4. Natsuko Suzui
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  5. Tatsuhiko Miyazaki
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  6. Yoko Aoki
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Contributions

AN, MO, and YA conceived the study and participated in its design. AN, TN, and YA performed the NGS and genetic analysis of the patients. NS and TM performed the pathological analysis. AN, MO, and YA wrote the paper. All authors read and approved the final paper.

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Correspondence to Michio Ozeki or Yoko Aoki.

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The authors declare that they have no conflict of interest.

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This study was approved by the Ethics Committees of the Gifu University School of Medicine and Tohoku University School of Medicine.

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Informed consent was obtained from the patients or their legal guardians for their inclusion in the study and subsequent publication.

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Nozawa, A., Ozeki, M., Niihori, T. et al. A somatic activating KRAS variant identified in an affected lesion of a patient with Gorham–Stout disease. J Hum Genet 65, 995–1001 (2020). https://doi.org/10.1038/s10038-020-0794-y

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