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Integrated Molecular Characterization of the Lethal Published OnlineFirst December 12, 2017; DOI: 10.1158/0008-5472.CAN-17-2581 Cancer Genome and Epigenome Research Integrated Molecular Characterization of the Lethal Pediatric Cancer Pancreatoblastoma Tomoya Isobe1, Masafumi Seki1, Kenichi Yoshida2, Masahiro Sekiguchi1, Yusuke Shiozawa1,2, Yuichi Shiraishi3, Shunsuke Kimura1,4, Misa Yoshida1,5, Yoshikage Inoue2, Akira Yokoyama2, Nobuyuki Kakiuchi2, Hiromichi Suzuki2, Keisuke Kataoka2, Yusuke Sato2, Tomoko Kawai6, Kenichi Chiba3, Hiroko Tanaka3, Teppei Shimamura7, Motohiro Kato8, Akihiro Iguchi9, Asahito Hama10, Tomoaki Taguchi11, Masaharu Akiyama12, Junya Fujimura13, Akiko Inoue14, Tsuyoshi Ito15, Takao Deguchi16, Chikako Kiyotani8, Tomoko Iehara17, Hajime Hosoi17, Akira Oka1, Masashi Sanada18, Yukichi Tanaka5, Kenichiro Hata6, Satoru Miyano3, Seishi Ogawa2, and Junko Takita1 Abstract Pancreatoblastoma is a rare pediatric pancreatic malignancy for (10%) was universally detected. At the transcriptome level, pan- which the molecular pathogenesis is not understood. In this creatoblastoma exhibited an expression profile characteristic of study, we report the findings of an integrated multiomics study early pancreas progenitor-like cells along with upregulation of the of whole-exome and RNA sequencing as well as genome-wide R-spondin/LGR5/RNF43 module. Our results offer a comprehen- copy number and methylation analyses of ten pancreatoblastoma sive description of the molecular basis for pancreatoblastoma and cases. The pancreatoblastoma genome was characterized by a high highlight rational therapeutic targets for its treatment. frequency of aberrant activation of the Wnt signaling pathway, Significance: Molecular genetic analysis of a rare untreatable either via somatic mutations of CTNNB1 (90%) and copy-neutral pediatric tumor reveals Wnt/IGF2 aberrations and features of early loss of heterozygosity (CN-LOH) of APC (10%). In addition, pancreas progenitor-like cells, suggesting cellular origins and ratio- imprinting dysregulation of IGF2 as a consequence of CN-LOH nal strategies for therapeutic targeting. Cancer Res; 78(4); 865–76. (80%), gain of paternal allele (10%), and gain of methylation Ó2017 AACR. 1Department of Pediatrics, Graduate School of Medicine, The University of Introduction 2 Tokyo, Tokyo, Japan. Department of Pathology and Tumor Biology, Graduate Pancreatoblastoma is a very rare pancreatic solid tumor that School of Medicine, Kyoto University, Kyoto, Japan. 3Laboratory of DNA Infor- mation Analysis, Human Genome Center, Institute of Medical Science, The typically affects young children, with a median age at diagnosis of University of Tokyo, Tokyo, Japan. 4Department of Pediatrics, Hiroshima Uni- 5 years. Including much less frequent adult cases, pancreatoblas- versity Graduate School of Biomedical Sciences, Hiroshima, Japan. 5Department toma comprises less than 1% of all pancreatic nonendocrine of Pathology, Kanagawa Children's Medical Center, Yokohama, Japan. 6Depart- tumors; despite its rarity, it is the most common malignant ment of Maternal-Fetal Biology, National Research Institute for Child Health and pancreatic tumor in children younger than 10 years (1). Morpho- 7 Development, Tokyo, Japan. Division of Systems Biology, Nagoya University logically, pancreatoblastoma resembles fetal pancreatic tissue at Graduate School of Medicine, Nagoya, Japan. 8Department of Pediatric Hema- tology and Oncology Research, National Research Institute for Child Health and gestational age of 8 weeks, manifesting multilineage elements with Development, Tokyo, Japan. 9Department of Pediatrics, Hokkaido University, acinar, ductal, and endocrine differentiation, which suggests a Sapporo, Japan. 10Department of Pediatrics, Nagoya University Graduate School primitive cellular origin of pancreatoblastoma (2). Owing to its of Medicine, Nagoya, Japan. 11Department of Pediatric Surgery, Graduate School rarity, optimized therapeutic strategies, including targeted thera- 12 of Medicine, Kyushu University, Fukuoka, Japan. Department of Pediatrics, pies, have not been established for pancreatoblastoma; only the 13 Jikei University School of Medicine, Tokyo, Japan. Department of Pediatrics, complete surgical resection is of proven prognostic value. Thus, Juntendo University School of Medicine, Tokyo, Japan. 14Department of Pedi- atrics, Osaka Medical College, Osaka, Japan. 15Department of Pediatrics, Toyo- children with unresectable or relapsed disease still have a very poor hashi Municipal Hospital, Toyohashi, Japan. 16Department of Pediatrics, Mie prognosis (3), which prompts a need for novel therapeutic modal- University Graduate School of Medicine, Tsu, Japan. 17Department of Pediatrics, ities based on a better understanding of its molecular pathogenesis. Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Several case studies have revealed recurrent alterations affecting 18 Kyoto, Japan. Clinical Research Center, National Hospital Organization Nagoya the Wnt/b-catenin pathway genes, including APC and CTNNB1 Medical Center, Nagoya, Japan. (encoding b-catenin), and a loss of heterozygosity (LOH) on Note: Supplementary data for this article are available at Cancer Research chromosome 11p in a subset of sporadic pancreatoblastoma Online (http://cancerres.aacrjournals.org/). (4, 5). Correspondingly, pancreatoblastoma cases associated with Corresponding Author: Junko Takita, Department of Pediatrics, Graduate familial adenomatous polyposis and Beckwith–Wiedemann syn- School of Medicine, The University of Tokyo, Hongo 7-3-1. Bunkyo-ku, Tokyo, drome (BWS) have also been reported (4, 6). In contrast, except 113-8655 Japan. Phone: 813-3815-5411; Fax: 813-3816-4108; E-mail: for only a few adult pancreatoblastoma cases exhibiting inacti- [email protected] vation of SMAD4 (7), mutations affecting KRAS, TP53, CDKN2A, doi: 10.1158/0008-5472.CAN-17-2581 and SMAD4, the four common targets of oncogenic events in Ó2017 American Association for Cancer Research. pancreatic ductal adenocarcinoma (PDAC), have not been www.aacrjournals.org 865 Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst December 12, 2017; DOI: 10.1158/0008-5472.CAN-17-2581 Isobe et al. reported in pancreatoblastoma (4). These clinicopathologic and score 20; (ii) base quality score 15; (iii) depths in both tumor genetic features suggest a distinctive oncogenic mechanism of this and normal 8; (iv) number of variant read pairs in the tumor 4; disease. However, because no comprehensive genomic studies (v) variant allele frequencies (VAF) in tumor samples 0.10; and À have been reported thus far, our knowledge about the molecular (vi) EBCall P 10 5. The following were further excluded: (i) basis of pancreatoblastoma is still very limited. synonymous single-nucleotide variants (SNV); (ii) mutations In this study, we analyzed 16 primary or metastatic tumor detected on only either the plus or minus strand; (iii) mutations specimens from 10 cases with pancreatoblastoma using tar- in HLA genes; (iv) SNVs listed in the NCBI dbSNP build 131 or our geted deep sequencing of 155 cancer driver genes, whole- in-house SNP database [SNVs with more than 10 entries in the exome sequencing (WES), RNA sequencing (RNA-seq), and Catalogue Of Somatic Mutations In Cancer (COSMIC) v70 were genome-wide copy number and methylation analyses. This not excluded]; (v) variants with 0.45 VAF 0.55 in copy-neutral multiomics approach allowed us to obtain a comprehensive regions; and (vi) variants detected in paired normal samples, if registry of the molecular lesions underlying the pathogenesis available, by Sanger sequencing. of pancreatoblastoma. WES and mutation calling Materials and Methods For WES, DNA libraries were prepared using SureSelect Human All Exon V5 (Agilent Technologies) according to the manufac- Subjects and samples turer's protocol. Enriched exome libraries were sequenced on an This study comprised 16 tumor samples from 10 Japanese Illumina HiSeq 2000 platform using 100-bp paired-end mode. patients with pancreatoblastoma, among which fresh-frozen Somatic variants were called by Genomon v2.3.0 with the fol- tumors were obtained from 6 patients, and for the remaining 4 lowing parameters: (i) mapping quality score 20; (ii) base patients, formalin-fixed paraffin-embedded (FFPE) samples were quality score 15; (iii) depths in both tumor and normal 8; procured. Written informed consent was obtained according to (iv) number of variant reads in the tumor 4; (v) VAFs in tumor protocols approved by the Human Genome, Gene Analysis samples 0.02; (vi) VAFs in normal samples <0.10; (vii) EBCall P À À Research Ethics Committee of the University of Tokyo, and other 10 5; and (viii) Fisher exact P 10 2. We further excluded (i) participating institutes. Matched peripheral blood samples were synonymous SNVs and (ii) SNVs listed in the NCBI dbSNP build obtained and used as germline controls for WES and amplicon 131 or our in-house SNP database. For subpopulation detection deep sequencing in 6 cases. For PBL001, a total of 7 samples (one and phylogenetic analysis of multiple samples from PBL001, from the primary, two from the second, and four from the third synonymous SNVs were retained and also subjected to the fol- surgery) were included. The diagnosis of pancreatoblastoma was lowing validation steps in this case. centrally reviewed and confirmed; staging was done based on fi WHO classi cation. All patients underwent surgery with or with- Validation of candidate
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