TY - JOUR
T1 - Integrated molecular characterization of the lethal pediatric cancer pancreatoblastoma
AU - Isobe, Tomoya
AU - Seki, Masafumi
AU - Yoshida, Kenichi
AU - Sekiguchi, Masahiro
AU - Shiozawa, Yusuke
AU - Shiraishi, Yuichi
AU - Kimura, Shunsuke
AU - Yoshida, Misa
AU - Inoue, Yoshikage
AU - Yokoyama, Akira
AU - Kakiuchi, Nobuyuki
AU - Suzuki, Hiromichi
AU - Kataoka, Keisuke
AU - Sato, Yusuke
AU - Kawai, Tomoko
AU - Chiba, Kenichi
AU - Tanaka, Hiroko
AU - Shimamura, Teppei
AU - Kato, Motohiro
AU - Iguchi, Akihiro
AU - Hama, Asahito
AU - Taguchi, Tomoaki
AU - Akiyama, Masaharu
AU - Fujimura, Junya
AU - Inoue, Akiko
AU - Ito, Tsuyoshi
AU - Deguchi, Takao
AU - Kiyotani, Chikako
AU - Iehara, Tomoko
AU - Hosoi, Hajime
AU - Oka, Akira
AU - Sanada, Masashi
AU - Tanaka, Yukichi
AU - Hata, Kenichiro
AU - Miyano, Satoru
AU - Ogawa, Seishi
AU - Takita, Junko
N1 - 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:
© 2017 American Association for Cancer Research.
PY - 2018/2/15
Y1 - 2018/2/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-17-2581
DO - 10.1158/0008-5472.CAN-17-2581
M3 - Article
C2 - 29233928
AN - SCOPUS:85042177230
SN - 0008-5472
VL - 78
SP - 865
EP - 876
JO - Cancer Research
JF - Cancer Research
IS - 4
ER -
