Recurrent neomorphic mutations of MTOR in central nervous system and testicular germ cell tumors may be targeted for therapy

Koichi Ichimura, Shintaro Fukushima, Yasushi Totoki, Yuko Matsushita, Ayaka Otsuka, Arata Tomiyama, Tohru Niwa, Hirokazu Takami, Taishi Nakamura, Tomonari Suzuki, Kohei Fukuoka, Takaaki Yanagisawa, Kazuhiko Mishima, Yoichi Nakazato, Fumie Hosoda, Yoshitaka Narita, Soichiro Shibui, Akihiko Yoshida, Akitake Mukasa, Nobuhito SaitoToshihiro Kumabe, Masayuki Kanamori, Teiji Tominaga, Keiichi Kobayashi, Saki Shimizu, Motoo Nagane, Toshihiko Iuchi, Masahiro Mizoguchi, Koji Yoshimoto, Kaoru Tamura, Taketoshi Maehara, Kazuhiko Sugiyama, Mitsutoshi Nakada, Keiichi Sakai, Yonehiro Kanemura, Masahiro Nonaka, Akio Asai, Kiyotaka Yokogami, Hideo Takeshima, Nobutaka Kawahara, Tatsuya Takayama, Masahiro Yao, Mamoru Kato, Hiromi Nakamura, Natsuko Hama, Ryuichi Sakai, Toshikazu Ushijima, Masao Matsutani, Tatsuhiro Shibata, Ryo Nishikawa

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Abstract

Germ cell tumors constitute a heterogeneous group that displays a broad spectrum of morphology. They often arise in testes; however, extragonadal occurrence, in particular brain, is not uncommon, and whether they share a common pathogenesis is unknown. We performed whole exome sequencing in 41 pairs of central nervous system germ cell tumors (CNS GCTs) of various histology and their matched normal tissues. We then performed targeted sequencing of 41 selected genes in a total of 124 CNS GCTs, 65 testicular germ cell tumors (tGCTs) and 8 metastatic GCTs to the CNS. The results showed that mutually exclusive mutations of genes involved in the MAPK pathway were most common (48.4 %), typically in KIT (27.4 %), followed by those in the PI3K pathway (12.9 %), particularly in MTOR (6.5 %), among the 124 CNS GCTs. Pure germinomas and non-germinomatous germ cell tumors (NGGCTs), as well as CNS and testicular GCTs, showed similar mutational profiles, suggesting that GCTs share a common molecular pathogenesis. Mutated MTOR identified in CNS GCTs upregulated phosphorylation of the AKT pathway proteins including AKT and 4EBP1 in nutrient-deprived conditions and enhanced soft-agar colony formation; both events were suppressed in a dose-dependent manner by addition of the MTOR inhibitor pp242. Our findings indicate that the dominant genetic drivers of GCTs regardless of the site of origin are activation of the MAPK and/or PI3K pathways by somatic point mutations. Mutated MTOR represents a potential target for novel targeted therapies for refractory GCTs.

Original languageEnglish
Pages (from-to)889-901
Number of pages13
JournalActa neuropathologica
Volume131
Issue number6
DOIs
Publication statusPublished - Jun 1 2016

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All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Ichimura, K., Fukushima, S., Totoki, Y., Matsushita, Y., Otsuka, A., Tomiyama, A., ... Nishikawa, R. (2016). Recurrent neomorphic mutations of MTOR in central nervous system and testicular germ cell tumors may be targeted for therapy. Acta neuropathologica, 131(6), 889-901. https://doi.org/10.1007/s00401-016-1557-x