TY - JOUR
T1 - Comprehensive genetic analysis of pediatric germ cell tumors identifies potential drug targets
AU - Kubota, Yasuo
AU - Seki, Masafumi
AU - Kawai, Tomoko
AU - Isobe, Tomoya
AU - Yoshida, Misa
AU - Sekiguchi, Masahiro
AU - Kimura, Shunsuke
AU - Watanabe, Kentaro
AU - Sato-Otsubo, Aiko
AU - Yoshida, Kenichi
AU - Suzuki, Hiromichi
AU - Kataoka, Keisuke
AU - Fujii, Yoichi
AU - Shiraishi, Yuichi
AU - Chiba, Kenichi
AU - Tanaka, Hiroko
AU - Hiwatari, Mitsuteru
AU - Oka, Akira
AU - Hayashi, Yasuhide
AU - Miyano, Satoru
AU - Ogawa, Seishi
AU - Hata, Kenichiro
AU - Tanaka, Yukichi
AU - Takita, Junko
N1 - Funding Information:
This work was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (KAKENHI; grant nos. JP17H04224, JP18K19467, and 20H00528 to J.T. and JP26221308 and JP19H05656 to S.O.); Project for Cancer Research and Therapeutic Evolution (P-CREATE; grant no. JP19cm0106509h9904 to J.T.), Project for Development of Innovative Research on Cancer Therapeutics (P-DIRECT; grant no. JP20cm0106501h0005 to S.O.), and Practical Research for Innovative Cancer Control (grant no. JP19ck0106468h0001 to J.T.) from Japan Agency for Medical Research and Development (AMED); Princess Takamatsu Cancer Research Fund (grant to J.T.); and Children’s Cancer Association of Japan (grant to Y Kubota). We are grateful to M. Matsumura, K. Yin, and F. Saito for their excellent technical assistance. We also wish to express our gratitude to M-J. Park (Gunma Children’s Medical Center), K. Koh (Saitama Children’s Medical Center), R. Hanada (Saitama Children’s Medical Center), C. Oyama (Shimane University), T. Taketani (Shimane University), and K. Kato (Ibaraki Children’s Hospital) for sample collection.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - To elucidate the molecular pathogenesis of pediatric germ cell tumors (GCTs), we performed DNA methylation array analysis, whole transcriptome sequencing, targeted capture sequencing, and single-nucleotide polymorphism array analysis using 51 GCT samples (25 female, 26 male), including 6 germinomas, 2 embryonal carcinomas, 4 immature teratomas, 3 mature teratomas, 30 yolk sac tumors, and 6 mixed germ cell tumors. Among the 51 samples, 11 were from infants, 23 were from young children, and 17 were from those aged ≥10 years. Sixteen of the 51 samples developed in the extragonadal regions. Germinomas showed upregulation of pluripotent genes and global hypomethylation. Pluripotent genes were also highly expressed in embryonal carcinomas. These genes may play essential roles in embryonal carcinomas given that their binding sites are hypomethylated. Yolk sac tumors exhibited overexpression of endodermal genes, such as GATA6 and FOXA2, the binding sites of which were hypomethylated. Interestingly, infant yolk sac tumors had different DNA methylation patterns from those observed in older children. Teratomas had higher expression of ectodermal genes, suggesting a tridermal nature. Based on our results, we suggest that KIT, TNFRSF8, and ERBB4 may be suitable targets for the treatment of germinoma, embryonal carcinomas, and yolk sac tumors, respectively.
AB - To elucidate the molecular pathogenesis of pediatric germ cell tumors (GCTs), we performed DNA methylation array analysis, whole transcriptome sequencing, targeted capture sequencing, and single-nucleotide polymorphism array analysis using 51 GCT samples (25 female, 26 male), including 6 germinomas, 2 embryonal carcinomas, 4 immature teratomas, 3 mature teratomas, 30 yolk sac tumors, and 6 mixed germ cell tumors. Among the 51 samples, 11 were from infants, 23 were from young children, and 17 were from those aged ≥10 years. Sixteen of the 51 samples developed in the extragonadal regions. Germinomas showed upregulation of pluripotent genes and global hypomethylation. Pluripotent genes were also highly expressed in embryonal carcinomas. These genes may play essential roles in embryonal carcinomas given that their binding sites are hypomethylated. Yolk sac tumors exhibited overexpression of endodermal genes, such as GATA6 and FOXA2, the binding sites of which were hypomethylated. Interestingly, infant yolk sac tumors had different DNA methylation patterns from those observed in older children. Teratomas had higher expression of ectodermal genes, suggesting a tridermal nature. Based on our results, we suggest that KIT, TNFRSF8, and ERBB4 may be suitable targets for the treatment of germinoma, embryonal carcinomas, and yolk sac tumors, respectively.
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U2 - 10.1038/s42003-020-01267-8
DO - 10.1038/s42003-020-01267-8
M3 - Article
C2 - 32999426
AN - SCOPUS:85091721932
SN - 2399-3642
VL - 3
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 544
ER -