Comprehensive genetic analysis of pediatric germ cell tumors identifies potential drug targets

Yasuo Kubota,Keisuke Kataoka,Seishi Ogawa,Kenichi Chiba,Satoru Miyano,Yukichi Tanaka,Tomoya Isobe,Kentaro Watanabe,Yuichi Shiraishi,Mutsuo Sekiguchi ,Aiko Sato‐Otsubo ,Kenichi Yoshida,Hiromichi Suzuki,Kenichiro Hata,Akira Oka,Misa Yoshida,Masafumi Seki,Yasuhide Hayashi,Shunsuke Kimura,Yoichi Fujii,Hiroko Tanaka,Tomoko Kawai,Mitsuteru Hiwatari,Junko Takita

doi:10.1038/s42003-020-01267-8

Abstract

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.

Highlights

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
While GCTs include several subtypes, such as seminoma, yolk sac tumors (YSTs), or embryonic carcinomas (ECs), they are dependent on the differential stages of PGCs10
We suggest that KIT, TNFRSF8, and ERBB4 may be suitable targets for the treatment of germinoma, ECs, and YSTs, respectively

Summary

Introduction

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. Migrating PGCs are chromosomally unstable due to DNA hypomethylation and are prone to developing copy number abnormalities or mutations[9]. Such aberrated PGCs are eliminated via apoptosis, a minority of aberrated PGCs survive and give rise to GCTs10. GCTs develop in the gonads and extragonads[11], such as the central nervous system (CNS), mediastinum, or sacrococcygeal regions, which are thought to be the migration routes of PGCs. While GCTs include several subtypes, such as seminoma, yolk sac tumors (YSTs), or embryonic carcinomas (ECs), they are dependent on the differential stages of PGCs10. Seminomas frequently exhibit an isochromosome of the short arm of chromosome 12 (isochromosome 12p) as well as mutations in KIT and RAS13

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Conclusion