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 Iguchi & 17 others Asahito 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

1 Citation (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

Fingerprint

Pediatrics
Loss of Heterozygosity
Neoplasms
Methylation
Pancreas
Stem Cells
Genome
Exome
RNA Sequence Analysis
Wnt Signaling Pathway
Transcriptome
Molecular Biology
Up-Regulation
Alleles
Pancreatoblastoma
Mutation
Therapeutics

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Isobe, T., Seki, M., Yoshida, K., Sekiguchi, M., Shiozawa, Y., Shiraishi, Y., ... 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

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

In: Cancer Research, Vol. 78, No. 4, 15.02.2018, p. 865-876.

Research output: Contribution to journalArticle

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, Iguchi, A, Hama, A, Taguchi, T, Akiyama, M, Fujimura, J, Inoue, A, Ito, T, Deguchi, T, Kiyotani, C, Iehara, T, Hosoi, H, Oka, A, Sanada, M, Tanaka, Y, Hata, K, Miyano, S, Ogawa, S & Takita, J 2018, 'Integrated molecular characterization of the lethal pediatric cancer pancreatoblastoma', Cancer Research, vol. 78, no. 4, pp. 865-876. https://doi.org/10.1158/0008-5472.CAN-17-2581
Isobe T, Seki M, Yoshida K, Sekiguchi M, Shiozawa Y, Shiraishi Y et al. Integrated molecular characterization of the lethal pediatric cancer pancreatoblastoma. Cancer Research. 2018 Feb 15;78(4):865-876. https://doi.org/10.1158/0008-5472.CAN-17-2581
Isobe, Tomoya ; Seki, Masafumi ; Yoshida, Kenichi ; Sekiguchi, Masahiro ; Shiozawa, Yusuke ; Shiraishi, Yuichi ; Kimura, Shunsuke ; Yoshida, Misa ; Inoue, Yoshikage ; Yokoyama, Akira ; Kakiuchi, Nobuyuki ; Suzuki, Hiromichi ; Kataoka, Keisuke ; Sato, Yusuke ; Kawai, Tomoko ; Chiba, Kenichi ; Tanaka, Hiroko ; Shimamura, Teppei ; Kato, Motohiro ; Iguchi, Akihiro ; Hama, Asahito ; Taguchi, Tomoaki ; Akiyama, Masaharu ; Fujimura, Junya ; Inoue, Akiko ; Ito, Tsuyoshi ; Deguchi, Takao ; Kiyotani, Chikako ; Iehara, Tomoko ; Hosoi, Hajime ; Oka, Akira ; Sanada, Masashi ; Tanaka, Yukichi ; Hata, Kenichiro ; Miyano, Satoru ; Ogawa, Seishi ; Takita, Junko. / Integrated molecular characterization of the lethal pediatric cancer pancreatoblastoma. In: Cancer Research. 2018 ; Vol. 78, No. 4. pp. 865-876.
@article{366b632183a14d738f896e78ce512571,
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",
year = "2018",
month = "2",
day = "15",
doi = "10.1158/0008-5472.CAN-17-2581",
language = "English",
volume = "78",
pages = "865--876",
journal = "Cancer Research",
issn = "0008-5472",
number = "4",

}

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

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.

UR - http://www.scopus.com/inward/record.url?scp=85042177230&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85042177230&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-17-2581

DO - 10.1158/0008-5472.CAN-17-2581

M3 - Article

VL - 78

SP - 865

EP - 876

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 4

ER -