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

被引：66

作者：

Ichimura, Koichi ^{[1
]}

Fukushima, Shintaro ^{[1
]}

Totoki, Yasushi ^{[2
]}

Matsushita, Yuko ^{[1
]}

Otsuka, Ayaka ^{[1
]}

Tomiyama, Arata ^{[3
]}

Niwa, Tohru ^{[4
]}

Takami, Hirokazu ^{[1
]}

Nakamura, Taishi ^{[1
,26
]}

Suzuki, Tomonari ^{[5
]}

Fukuoka, Kohei ^{[1
,5
]}

Yanagisawa, Takaaki ^{[5
,30
]}

Mishima, Kazuhiko ^{[5
]}

Nakazato, Yoichi ^{[6
]}

Hosoda, Fumie ^{[2
]}

Narita, Yoshitaka ^{[7
]}

Shibui, Soichiro ^{[7
]}

Yoshida, Akihiko ^{[8
,9
]}

Mukasa, Akitake ^{[10
,11
]}

Saito, Nobuhito ^{[10
,11
]}

Kumabe, Toshihiro ^{[12
,13
]}

Kanamori, Masayuki ^{[12
]}

Tominaga, Teiji ^{[12
]}

Kobayashi, Keiichi

Shimizu, Saki ^{[14
]}

Nagane, Motoo ^{[14
]}

Iuchi, Toshihiko ^{[15
]}

Mizoguchi, Masahiro ^{[16
]}

Yoshimoto, Koji ^{[16
]}

Tamura, Kaoru ^{[17
]}

Maehara, Taketoshi ^{[17
]}

Sugiyama, Kazuhiko ^{[18
,19
]}

Nakada, Mitsutoshi ^{[20
]}

Sakai, Keiichi ^{[21
]}

Kanemura, Yonehiro

Nonaka, Masahiro ^{[22
,23
]}

Asai, Akio ^{[24
]}

Yokogami, Kiyotaka ^{[25
]}

Takeshima, Hideo ^{[25
]}

Kawahara, Nobutaka ^{[26
]}

Takayama, Tatsuya ^{[27
,29
]}

Yao, Masahiro ^{[28
]}

Kato, Mamoru ^{[2
]}

Nakamura, Hiromi ^{[2
]}

Hama, Natsuko ^{[2
]}

Sakai, Ryuichi ^{[3
]}

Ushijima, Toshikazu ^{[4
]}

Matsutani, Masao

Shibata, Tatsuhiro ^{[2
,31
]}

Nishikawa, Ryo ^{[5
]}

机构：

[1] Natl Canc Ctr, Div Brain Tumor Translat Res, Chuo Ku, 5-1-1 Tsukiji, Tokyo 1040045, Japan

[2] Natl Canc Ctr, Res Inst, Div Canc Genom, Tokyo 104, Japan

[3] Natl Canc Ctr, Res Inst, Div Refractory & Adv Canc, Tokyo 104, Japan

[4] Natl Canc Ctr, Res Inst, Div Epigen, Tokyo 104, Japan

[5] Saitama Med Univ, Dept Neurooncol Neurosurg, Int Med Ctr, Hidaka, Japan

[6] Hidaka Hosp, Dept Pathol, Takasaki, Gunma, Japan

[7] Natl Canc Ctr, Dept Neurosurg & Neurooncol, 1-1 Tsukiji 5 chome, Tokyo, Japan

[8] Natl Canc Ctr, Dept Pathol, 1-1 Tsukiji 5 chome, Tokyo, Japan

[9] Natl Canc Ctr, Clin Labs, 1-1 Tsukiji 5 chome, Tokyo, Japan

[10] Univ Tokyo, Dept Neurosurg, Grad Sch, Tokyo, Japan

[11] Fac Med, Tokyo, Japan

[12] Tohoku Univ, Grad Sch Med, Dept Neurosurg, Sendai, Miyagi 980, Japan

[13] Kitasato Univ, Dept Neurosurg, Sch Med, Sagamihara, Kanagawa 228, Japan

[14] Kyorin Univ, Fac Med, Dept Neurosurg, Tokyo, Japan

[15] Chiba Canc Ctr, Dept Neurosurg, 666-2 Nitonacho, Chiba 2608717, Japan

[16] Kyushu Univ, Dept Neurosurg, Grad Sch Med Sci, Fukuoka 812, Japan

[17] Tokyo Med & Dent Univ, Dept Neurosurg, Grad Sch Med & Dent Sci, Tokyo, Japan

[18] Hiroshima Univ Hosp, Dept Clin Oncol, Hiroshima, Japan

[19] Hiroshima Univ Hosp, Neurooncol Program, Hiroshima, Japan

[20] Kanazawa Univ, Grad Sch Med Sci, Dept Neurosurg, Kanazawa, Ishikawa, Japan

[21] Shinshu Ueda Med Ctr, Dept Neurosurg, Ueda, Nagano, Japan

[22] Osaka Natl Hosp, Dept Neurosurg, Osaka, Japan

[23] Osaka Natl Hosp, Inst Clin Res, Osaka, Japan

[24] Kansai Med Univ, Hirakata Hosp, Dept Neurosurg, Hirakata, Osaka, Japan

[25] Miyazaki Univ, Fac Med, Dept Neurosurg, Miyazaki, Japan

[26] Yokohama City Univ, Dept Neurosurg, Fac Med, Yokohama, Kanagawa 232, Japan

[27] Hamamatsu Univ, Sch Med, Dept Urol, Hamamatsu, Shizuoka, Japan

[28] Yokohama City Univ, Dept Urol, Grad Sch Med, Yokohama, Kanagawa 232, Japan

[29] Jichi Med Univ, Dept Urol, Sch Med, Shimotsuke, Japan

[30] Jikei Univ, Dept Neurosurg, Sch Med, Tokyo, Japan

[31] Univ Tokyo, Inst Med Sci, Mol Med Lab, Ctr Human Genome, Tokyo, Japan

来源：

ACTA NEUROPATHOLOGICA | 2016年 / 131卷 / 06期

关键词：

CNS germ cell tumors; Germinoma; NGGCT; MTOR; MAPK; CARCINOMA; KIT;

D O I：

10.1007/s00401-016-1557-x

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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.

引用

页码：889 / 901

页数：13

共 25 条

[21] Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma [J].

Taylor, Kathryn R. ;

Mackay, Alan ;

Truffaux, Nathalene ;

Butterfield, Yaron S. ;

Morozova, Olena ;

Philippe, Cathy ;

Castel, David ;

Grasso, Catherine S. ;

Vinci, Maria ;

Carvalho, Diana ;

Carcaboso, Angel M. ;

de Torres, Carmen ;

Cruz, Ofelia ;

Mora, Jaume ;

Entz-Werle, Natacha ;

Ingram, Wendy J. ;

Monje, Michelle ;

Hargrave, Darren ;

Bullock, Alex N. ;

Puget, Stephanie ;

Yip, Stephen ;

Jones, Chris ;

Grill, Jacques .

NATURE GENETICS, 2014, 46 (05) :457-461

[22] CLASSIFICATION OF ENDODERMAL SINUS TUMOUR (MESOBLASTOMA VITELLINUM) AND SO-CALLED EMBRYONAL CARCINOMA OF OVARY [J].

TEILUM, G .

ACTA PATHOLOGICA ET MICROBIOLOGICA SCANDINAVICA, 1965, 64 (04) :407-&

[23] Trans-ancestry mutational landscape of hepatocellular carcinoma genomes [J].

Totoki, Yasushi ;

Tatsuno, Kenji ;

Covington, Kyle R. ;

Ueda, Hiroki ;

Creighton, Chad J. ;

Kato, Mamoru ;

Tsuji, Shingo ;

Donehower, Lawrence A. ;

Slagle, Betty L. ;

Nakamura, Hiromi ;

Yamamoto, Shogo ;

Shinbrot, Eve ;

Hama, Natsuko ;

Lehmkuhl, Megan ;

Hosoda, Fumie ;

Arai, Yasuhito ;

Walker, Kim ;

Dahdouli, Mahmoud ;

Gotoh, Kengo ;

Nagae, Genta ;

Gingras, Marie-Claude ;

Muzny, Donna M. ;

Ojima, Hidenori ;

Shimada, Kazuaki ;

Midorikawa, Yutaka ;

Goss, John A. ;

Cotton, Ronald ;

Hayashi, Akimasa ;

Shibahara, Junji ;

Ishikawa, Shumpei ;

Guiteau, Jacfranz ;

Tanaka, Mariko ;

Urushidate, Tomoko ;

Ohashi, Shoko ;

Okada, Naoko ;

Doddapaneni, Harsha ;

Wang, Min ;

Zhu, Yiming ;

Huyen Dinh ;

Okusaka, Takuji ;

Kokudo, Norihiro ;

Kosuge, Tomoo ;

Takayama, Tadatoshi ;

Fukayama, Masashi ;

Gibbs, Richard A. ;

Wheeler, David A. ;

Aburatani, Hiroyuki ;

Shibata, Tatsuhiro .

NATURE GENETICS, 2014, 46 (12) :1267-1273

[24] Novel somatic and germline mutations in intracranial germ cell tumours [J].

Wang, Linghua ;

Yamaguchi, Shigeru ;

Burstein, Matthew D. ;

Terashima, Keita ;

Chang, Kyle ;

Ng, Ho-Keung ;

Nakamura, Hideo ;

He, Zongxiao ;

Doddapaneni, Harshavardhan ;

Lewis, Lora ;

Wang, Mark ;

Suzuki, Tomonari ;

Nishikawa, Ryo ;

Natsume, Atsushi ;

Terasaka, Shunsuke ;

Dauser, Robert ;

Whitehead, William ;

Adekunle, Adesina ;

Sun, Jiayi ;

Qiao, Yi ;

Marth, Gabor ;

Muzny, Donna M. ;

Gibbs, Richard A. ;

Leal, Suzanne M. ;

Wheeler, David A. ;

Lau, Ching C. .

NATURE, 2014, 511 (7508) :241-+

[25] Two-stage PCR protocol allowing introduction of multiple mutations, deletions and insertions using QuikChange™ site-directed mutagenesis [J].

Wang, WY ;

Malcolm, BA .

BIOTECHNIQUES, 1999, 26 (04) :680-682

← 1 2 3 →