Integrated molecular characterization of the lethal pediatric cancer pancreatoblastoma

Tomoya Isobe, Masafumi Seki, Kenichi Yoshida, Masahiro Sekiguchi, Yusuke Shiozawa, Yuichi Shiraishi, Shunsuke Kimura, Misa Yoshida, Yoshikage Inoue, Akira Yokoyama, Nobuyuki Kakiuchi, Hiromichi Suzuki, Keisuke Kataoka, Yusuke Sato, Tomoko Kawai, Kenichi Chiba, Hiroko Tanaka, Teppei Shimamura, Motohiro Kato, Akihiro IguchiAsahito Hama, Tomoaki Taguchi, Masaharu Akiyama, Junya Fujimura, Akiko Inoue, Tsuyoshi Ito, Takao Deguchi, Chikako Kiyotani, Tomoko Iehara, Hajime Hosoi, Akira Oka, Masashi Sanada, Yukichi Tanaka, Kenichiro Hata, Satoru Miyano, Seishi Ogawa, Junko Takita

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)865-876
Number of pages12
JournalCancer Research
Volume78
Issue number4
DOIs
Publication statusPublished - Feb 15 2018

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Isobe, T., Seki, M., Yoshida, K., Sekiguchi, M., Shiozawa, Y., Shiraishi, Y., Kimura, S., Yoshida, M., Inoue, Y., Yokoyama, A., Kakiuchi, N., Suzuki, H., Kataoka, K., Sato, Y., Kawai, T., Chiba, K., Tanaka, H., Shimamura, T., Kato, M., ... Takita, J. (2018). Integrated molecular characterization of the lethal pediatric cancer pancreatoblastoma. Cancer Research, 78(4), 865-876. https://doi.org/10.1158/0008-5472.CAN-17-2581