@article{e43d4ece710d4f75b50d6ba09c9c991c,
title = "Integrated molecular characterization of the lethal pediatric cancer pancreatoblastoma",
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.",
author = "Tomoya Isobe and Masafumi Seki and Kenichi Yoshida and Masahiro Sekiguchi and Yusuke Shiozawa and Yuichi Shiraishi and Shunsuke Kimura and Misa Yoshida and Yoshikage Inoue and Akira Yokoyama and Nobuyuki Kakiuchi and Hiromichi Suzuki and Keisuke Kataoka and Yusuke Sato and Tomoko Kawai and Kenichi Chiba and Hiroko Tanaka and Teppei Shimamura and Motohiro Kato and Akihiro Iguchi and Asahito Hama and Tomoaki Taguchi and Masaharu Akiyama and Junya Fujimura and Akiko Inoue and Tsuyoshi Ito and Takao Deguchi and Chikako Kiyotani and Tomoko Iehara and Hajime Hosoi and Akira Oka and Masashi Sanada and Yukichi Tanaka and Kenichiro Hata and Satoru Miyano and Seishi Ogawa and Junko Takita",
note = "Funding Information: We gratefully acknowledge the GTEx Project and all its contributing investigators for making the invaluable data publicly available. The datasets used for the analyses described in this article were obtained from dbGaP at http://www. ncbi.nlm.nih.gov/gap through dbGaP accession number phs000424.v6.p1. We are also grateful to Ms. Matsumura, Ms. Hoshino, Ms. Yin, Ms. Saito, Ms. Mizota, Ms. Nakamura, and Ms. Iijima for their excellent technical assistance. We also wish to express our appreciation to Drs. J. Mitsui and S. Tsuji, The University of Tokyo, for next-generation sequencing. This work was supported by KAKENHI (26293242 to J. Takita) from Japan Society for the Promotion of Science; by Research on Measures for Intractable Diseases, Health and Labor Sciences Research Grants, Ministry of Health, Labor and Welfare (to J. Takita); by Research on Health Sciences focusing on Drug Innovation (to J. Takita); by the Japan Health Sciences Foundation (to J. Takita); by Core Research for Evolutional Science and Technology, Japan Science and Technology Agency (to J. Takita); by Japan Agency for Medical Research and Development (AMED) Project for Cancer Research and Therapeutic Evolution (P-CREATE; to J. Takita); and by Pancreas Research Foundation of Japan (to T. Isobe). Funding Information: We gratefully acknowledge the GTEx Project and all its contributing investigators for making the invaluable data publicly available. The datasets used for the analyses described in this article were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000424.v6.p1. We are also grateful to Ms. Matsumura, Ms. Hoshino, Ms. Yin, Ms. Saito, Ms. Mizota, Ms. Nakamura, and Ms. Iijima for their excellent technical assistance. We also wish to express our appreciation to Drs. J. Mitsui and S. Tsuji, The University of Tokyo, for next-generation sequencing. This work was supported by KAKENHI (26293242 to J. Takita) from Japan Society for the Promotion of Science; by Research on Measures for Intractable Diseases, Health and Labor Sciences Research Grants, Ministry of Health, Labor and Welfare (to J. Takita); by Research on Health Sciences focusing on Drug Innovation (to J. Takita); by the Japan Health Sciences Foundation (to J. Takita); by Core Research for Evolutional Science and Technology, Japan Science and Technology Agency (to J. Takita); by Japan Agency for Medical Research and Development (AMED) Project for Cancer Research and Therapeutic Evolution (P-CREATE; to J. Takita); and by Pancreas Research Foundation of Japan (to T. Isobe). Publisher Copyright: {\textcopyright} 2017 American Association for Cancer Research.",
year = "2018",
month = feb,
day = "15",
doi = "10.1158/0008-5472.CAN-17-2581",
language = "English",
volume = "78",
pages = "865--876",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "4",
}
SDG 3 Good Health and Well-being