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Integrated Molecular Characterization of the Lethal Pediatric Cancer Pancreatoblastoma

Authors :
Yukichi Tanaka
Tomoya Isobe
Motohiro Kato
Hajime Hosoi
Yoshikage Inoue
Kenichiro Hata
Takao Deguchi
Chikako Kiyotani
Masafumi Seki
Hiromichi Suzuki
Tsuyoshi Ito
Akihiro Iguchi
Yuichi Shiraishi
Tomoko Iehara
Satoru Miyano
Yusuke Sato
Yusuke Shiozawa
Junko Takita
Hiroko Tanaka
Akira Yokoyama
Masahiro Sekiguchi
Shunsuke Kimura
Keisuke Kataoka
Akiko Inoue
Asahito Hama
Teppei Shimamura
Junya Fujimura
Tomoaki Taguchi
Tomoko Kawai
Misa Yoshida
Masaharu Akiyama
Akira Oka
Nobuyuki Kakiuchi
Masashi Sanada
Kenichi Chiba
Kenichi Yoshida
Seishi Ogawa
Source :
Cancer research. 78(4)
Publication Year :
2017

Abstract

Pancreatoblastoma is a rare pediatric pancreatic malignancy for which the molecular pathogenesis is not understood. In this study, we report the findings of an integrated multiomics study of whole-exome and RNA sequencing as well as genome-wide copy number and methylation analyses of ten pancreatoblastoma cases. The pancreatoblastoma genome was characterized by a high frequency of aberrant activation of the Wnt signaling pathway, either via somatic mutations of CTNNB1 (90%) and copy-neutral loss of heterozygosity (CN-LOH) of APC (10%). In addition, imprinting dysregulation of IGF2 as a consequence of CN-LOH (80%), gain of paternal allele (10%), and gain of methylation (10%) was universally detected. At the transcriptome level, pancreatoblastoma exhibited an expression profile characteristic of early pancreas progenitor-like cells along with upregulation of the R-spondin/LGR5/RNF43 module. Our results offer a comprehensive description of the molecular basis for pancreatoblastoma and highlight rational therapeutic targets for its treatment. Significance: Molecular genetic analysis of a rare untreatable pediatric tumor reveals Wnt/IGF2 aberrations and features of early pancreas progenitor-like cells, suggesting cellular origins and rational strategies for therapeutic targeting. Cancer Res; 78(4); 865–76. ©2017 AACR.

Details

ISSN :
15387445
Volume :
78
Issue :
4
Database :
OpenAIRE
Journal :
Cancer research
Accession number :
edsair.doi.dedup.....61a83bb232a1c95f78c74a28912c43d1