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Mutually exclusive mutations of KIT and RAS are associated with KIT mRNA expression and chromosomal instability in primary intracranial pure germinomas

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Abstract

Intracranial germ cell tumors (iGCTs) are the second most common brain tumors among children under 15 in Japan. The pathogenesis of iGCTs is largely unexplored. Although a subset of iGCTs is known to have KIT mutation, its impact on the biology and patients’ survival has not been established. In this study, we investigated genes involved in the KIT signaling pathway. 65 iGCTs (30 pure germinomas, 14 teratomas, 18 mixed GCTs, 2 yolk sac tumors, 1 choriocarcinoma) were screened for mutation of KIT, KRAS, NRAS, HRAS, BRAF, PDGFRA, and IDH1 by direct sequencing. KIT expression was examined by immunohistochemistry and quantitative PCR. Chromosomal status was analyzed by array-comparative genomic hybridization (aCGH). Somatic mutations were detected only in KIT and RAS, which were frequently observed in pure germinomas (60.0 %), but rare in non-germinomatous GCTs (NGGCTs) (8.6 %). All KIT/RAS mutations were mutually exclusive. Regardless of the mutation status or mRNA expression, the KIT protein was expressed in all germinomas, while only in 54.3 % of NGGCTs. Amplification of KIT was found in one pure germinoma by aCGH. In pure germinomas, high expression of KIT mRNA was associated with the presence of KIT/RAS alterations and severe chromosomal instability. Our results indicate that alterations of the KIT signaling pathway play an important role in the development of germinomas. Pure germinomas may develop through two distinct pathogeneses: one with KIT/RAS alterations, elevated KIT mRNA expression and severe chromosomal instability, and the other through yet an unidentified mechanism without any of the above abnormalities.

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Acknowledgments

We are grateful to Dr. Yasuhito Arai, Cancer Genomics Division, National Cancer Center Research Institute for providing valuable assistance in the aCGH experiment, Hiromi Nakamura, Department of Bioinformatics, National Cancer Center Research Institute for her assistance with the bioinformatics analysis of the aCGH data, and Dr. Reika Iwakawa, Biology Division, National Cancer Center Research Institute for technical assistance with direct sequencing. We thank all the participating institutions of the iGCT Consortium for their valuable support and contributions. This study was carried out as a research program of the Project for Development of Innovative Research on Cancer Therapeutics (P-Direct) Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan. S.F. is an awardee of a Research Resident Fellowship from the Foundation for Promotion of Cancer Research (Japan) for the 3rd Term Comprehensive 10-year Strategy for Cancer Control.

Conflict of interest

We declare that we have no conflict of interest to carry out this investigation.

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Authors and Affiliations

  1. Division of Brain Tumor Translational Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Shintaro Fukushima, Ayaka Otsuka & Koichi Ichimura

  2. Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan

    Tomonari Suzuki, Kazuhiko Mishima, Masao Matsutani & Ryo Nishikawa

  3. Division of Pediatric Neuro-Oncology, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan

    Takaaki Yanagisawa

  4. Department of Neurosurgery, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Akitake Mukasa & Nobuhito Saito

  5. Department of Neurosurgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan

    Masayuki Kanamori & Teiji Tominaga

  6. Department of Neurosurgery, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan

    Toshihiro Kumabe

  7. Department of Neurosurgery and Neurooncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Yoshitaka Narita & Soichiro Shibui

  8. Department of Bioinformatics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Mamoru Kato

  9. Division of Cancer Genomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Tatsuhiro Shibata

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  1. Shintaro Fukushima
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  2. Ayaka Otsuka
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  17. Koichi Ichimura
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On behalf of the Intracranial Germ Cell Tumor Genome Analysis Consortium (iGCT Consortium)

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Correspondence to Koichi Ichimura.

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Fukushima, S., Otsuka, A., Suzuki, T. et al. Mutually exclusive mutations of KIT and RAS are associated with KIT mRNA expression and chromosomal instability in primary intracranial pure germinomas. Acta Neuropathol 127, 911–925 (2014). https://doi.org/10.1007/s00401-014-1247-5

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