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

研究成果: ジャーナルへの寄稿記事

12 引用 (Scopus)

抄録

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.

元の言語英語
ページ(範囲)889-901
ページ数13
ジャーナルActa neuropathologica
131
発行部数6
DOI
出版物ステータス出版済み - 6 1 2016

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Germ Cell and Embryonal Neoplasms
Nervous System Neoplasms
Central Nervous System
Mutation
Phosphatidylinositol 3-Kinases
Therapeutics
Germinoma
Exome
Point Mutation
Genes
Agar
Testicular Germ Cell Tumor
Testis
Histology
Phosphorylation
Food
Brain
Proteins

All Science Journal Classification (ASJC) codes

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

これを引用

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

Recurrent neomorphic mutations of MTOR in central nervous system and testicular germ cell tumors may be targeted for therapy. / Ichimura, Koichi; Fukushima, Shintaro; Totoki, Yasushi; Matsushita, Yuko; Otsuka, Ayaka; Tomiyama, Arata; Niwa, Tohru; Takami, Hirokazu; Nakamura, Taishi; Suzuki, Tomonari; Fukuoka, Kohei; Yanagisawa, Takaaki; Mishima, Kazuhiko; Nakazato, Yoichi; Hosoda, Fumie; Narita, Yoshitaka; Shibui, Soichiro; Yoshida, Akihiko; Mukasa, Akitake; Saito, Nobuhito; Kumabe, Toshihiro; Kanamori, Masayuki; Tominaga, Teiji; Kobayashi, Keiichi; Shimizu, Saki; Nagane, Motoo; Iuchi, Toshihiko; Mizoguchi, Masahiro; Yoshimoto, Koji; Tamura, Kaoru; Maehara, Taketoshi; Sugiyama, Kazuhiko; Nakada, Mitsutoshi; Sakai, Keiichi; Kanemura, Yonehiro; Nonaka, Masahiro; Asai, Akio; Yokogami, Kiyotaka; Takeshima, Hideo; Kawahara, Nobutaka; Takayama, Tatsuya; Yao, Masahiro; Kato, Mamoru; Nakamura, Hiromi; Hama, Natsuko; Sakai, Ryuichi; Ushijima, Toshikazu; Matsutani, Masao; Shibata, Tatsuhiro; Nishikawa, Ryo.

:: Acta neuropathologica, 巻 131, 番号 6, 01.06.2016, p. 889-901.

研究成果: ジャーナルへの寄稿記事

Ichimura, K, Fukushima, S, Totoki, Y, Matsushita, Y, Otsuka, A, Tomiyama, A, Niwa, T, Takami, H, Nakamura, T, Suzuki, T, Fukuoka, K, Yanagisawa, T, Mishima, K, Nakazato, Y, Hosoda, F, Narita, Y, Shibui, S, Yoshida, A, Mukasa, A, Saito, N, Kumabe, T, Kanamori, M, Tominaga, T, Kobayashi, K, Shimizu, S, Nagane, M, Iuchi, T, Mizoguchi, M, Yoshimoto, K, Tamura, K, Maehara, T, Sugiyama, K, Nakada, M, Sakai, K, Kanemura, Y, Nonaka, M, Asai, A, Yokogami, K, Takeshima, H, Kawahara, N, Takayama, T, Yao, M, Kato, M, Nakamura, H, Hama, N, Sakai, R, Ushijima, T, Matsutani, M, Shibata, T & Nishikawa, R 2016, 'Recurrent neomorphic mutations of MTOR in central nervous system and testicular germ cell tumors may be targeted for therapy', Acta neuropathologica, 巻. 131, 番号 6, pp. 889-901. https://doi.org/10.1007/s00401-016-1557-x
Ichimura, Koichi ; Fukushima, Shintaro ; Totoki, Yasushi ; Matsushita, Yuko ; Otsuka, Ayaka ; Tomiyama, Arata ; Niwa, Tohru ; Takami, Hirokazu ; Nakamura, Taishi ; Suzuki, Tomonari ; Fukuoka, Kohei ; Yanagisawa, Takaaki ; Mishima, Kazuhiko ; Nakazato, Yoichi ; Hosoda, Fumie ; Narita, Yoshitaka ; Shibui, Soichiro ; Yoshida, Akihiko ; Mukasa, Akitake ; Saito, Nobuhito ; Kumabe, Toshihiro ; Kanamori, Masayuki ; Tominaga, Teiji ; Kobayashi, Keiichi ; Shimizu, Saki ; Nagane, Motoo ; Iuchi, Toshihiko ; Mizoguchi, Masahiro ; Yoshimoto, Koji ; Tamura, Kaoru ; Maehara, Taketoshi ; Sugiyama, Kazuhiko ; Nakada, Mitsutoshi ; Sakai, Keiichi ; Kanemura, Yonehiro ; Nonaka, Masahiro ; Asai, Akio ; Yokogami, Kiyotaka ; Takeshima, Hideo ; Kawahara, Nobutaka ; Takayama, Tatsuya ; Yao, Masahiro ; Kato, Mamoru ; Nakamura, Hiromi ; Hama, Natsuko ; Sakai, Ryuichi ; Ushijima, Toshikazu ; Matsutani, Masao ; Shibata, Tatsuhiro ; Nishikawa, Ryo. / Recurrent neomorphic mutations of MTOR in central nervous system and testicular germ cell tumors may be targeted for therapy. :: Acta neuropathologica. 2016 ; 巻 131, 番号 6. pp. 889-901.
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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.",
author = "Koichi Ichimura and Shintaro Fukushima and Yasushi Totoki and Yuko Matsushita and Ayaka Otsuka and Arata Tomiyama and Tohru Niwa and Hirokazu Takami and Taishi Nakamura and Tomonari Suzuki and Kohei Fukuoka and Takaaki Yanagisawa and Kazuhiko Mishima and Yoichi Nakazato and Fumie Hosoda and Yoshitaka Narita and Soichiro Shibui and Akihiko Yoshida and Akitake Mukasa and Nobuhito Saito and Toshihiro Kumabe and Masayuki Kanamori and Teiji Tominaga and Keiichi Kobayashi and Saki Shimizu and Motoo Nagane and Toshihiko Iuchi and Masahiro Mizoguchi and Koji Yoshimoto and Kaoru Tamura and Taketoshi Maehara and Kazuhiko Sugiyama and Mitsutoshi Nakada and Keiichi Sakai and Yonehiro Kanemura and Masahiro Nonaka and Akio Asai and Kiyotaka Yokogami and Hideo Takeshima and Nobutaka Kawahara and Tatsuya Takayama and Masahiro Yao and Mamoru Kato and Hiromi Nakamura and Natsuko Hama and Ryuichi Sakai and Toshikazu Ushijima and Masao Matsutani and Tatsuhiro Shibata and Ryo Nishikawa",
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T1 - Recurrent neomorphic mutations of MTOR in central nervous system and testicular germ cell tumors may be targeted for therapy

AU - Ichimura, Koichi

AU - Fukushima, Shintaro

AU - Totoki, Yasushi

AU - Matsushita, Yuko

AU - Otsuka, Ayaka

AU - Tomiyama, Arata

AU - Niwa, Tohru

AU - Takami, Hirokazu

AU - Nakamura, Taishi

AU - Suzuki, Tomonari

AU - Fukuoka, Kohei

AU - Yanagisawa, Takaaki

AU - Mishima, Kazuhiko

AU - Nakazato, Yoichi

AU - Hosoda, Fumie

AU - Narita, Yoshitaka

AU - Shibui, Soichiro

AU - Yoshida, Akihiko

AU - Mukasa, Akitake

AU - Saito, Nobuhito

AU - Kumabe, Toshihiro

AU - Kanamori, Masayuki

AU - Tominaga, Teiji

AU - Kobayashi, Keiichi

AU - Shimizu, Saki

AU - Nagane, Motoo

AU - Iuchi, Toshihiko

AU - Mizoguchi, Masahiro

AU - Yoshimoto, Koji

AU - Tamura, Kaoru

AU - Maehara, Taketoshi

AU - Sugiyama, Kazuhiko

AU - Nakada, Mitsutoshi

AU - Sakai, Keiichi

AU - Kanemura, Yonehiro

AU - Nonaka, Masahiro

AU - Asai, Akio

AU - Yokogami, Kiyotaka

AU - Takeshima, Hideo

AU - Kawahara, Nobutaka

AU - Takayama, Tatsuya

AU - Yao, Masahiro

AU - Kato, Mamoru

AU - Nakamura, Hiromi

AU - Hama, Natsuko

AU - Sakai, Ryuichi

AU - Ushijima, Toshikazu

AU - Matsutani, Masao

AU - Shibata, Tatsuhiro

AU - Nishikawa, Ryo

PY - 2016/6/1

Y1 - 2016/6/1

N2 - 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.

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