Integrated Molecular Characterization of the Lethal

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Integrated Molecular Characterization of the Lethal Author Manuscript Published OnlineFirst on December 12, 2017; DOI: 10.1158/0008-5472.CAN-17-2581 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Integrated molecular characterization of the lethal pediatric cancer 2 pancreatoblastoma 3 4 Tomoya Isobe1, Masafumi Seki1, Kenichi Yoshida2, Masahiro Sekiguchi1, Yusuke Shiozawa1,2, 5 Yuichi Shiraishi3, Shunsuke Kimura1,4, Misa Yoshida1,5, Yoshikage Inoue2, Akira Yokoyama2, 6 Nobuyuki Kakiuchi2, Hiromichi Suzuki2, Keisuke Kataoka2, Yusuke Sato2, Tomoko Kawai6, 7 Kenichi Chiba3, Hiroko Tanaka3, Teppei Shimamura7, Motohiro Kato8, Akihiro Iguchi9, 8 Asahito Hama10, Tomoaki Taguchi11, Masaharu Akiyama12, Junya Fujimura13, Akiko Inoue14, 9 Tsuyoshi Ito15, Takao Deguchi16, Chikako Kiyotani8, Tomoko Iehara17, Hajime Hosoi17, 10 Akira Oka1, Masashi Sanada18, Yukichi Tanaka5, Kenichiro Hata6, Satoru Miyano3, Seishi 11 Ogawa2, Junko Takita1 12 13 1Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, 14 Japan; 2Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto 15 University, Kyoto, Japan; 3Laboratory of DNA Information Analysis, Human Genome Center, 16 Institute of Medical Science, The University of Tokyo, Tokyo, Japan; 4Department of 17 Pediatrics, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, 18 Japan; 5Department of Pathology, Kanagawa Children’s Medical Center, Yokohama, Japan; 19 6Department of Maternal-Fetal Biology, National Research Institute for Child Health and 20 Development, Tokyo, Japan; 7Division of Systems Biology, Nagoya University Graduate 21 School of Medicine, Nagoya, Japan; 8Department of Pediatric Hematology and Oncology 22 Research, National Research Institute for Child Health and Development, Tokyo, Japan; 23 9Department of Pediatrics, Hokkaido University, Sapporo, Japan; 10Department of 24 Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan; 11Department 25 of Pediatric Surgery, Graduate School of Medicine, Kyushu University, Fukuoka, Japan; 26 12Department of Pediatrics, Jikei University School of Medicine, Tokyo, Japan; 27 13Department of Pediatrics, Juntendo University School of Medicine, Tokyo, Japan; 28 14Department of Pediatrics, Osaka Medical College, Osaka, Japan; 15Department of 29 Pediatrics, Toyohashi Municipal Hospital, Toyohashi, Japan; 16Department of Pediatrics, 30 Mie University Graduate School of Medicine, Tsu, Japan; 17Department of Pediatrics, 31 Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, 32 Japan; 18Clinical Research Center, National Hospital Organization Nagoya Medical Center, 33 Nagoya, Japan. 34 35 Running Title 36 Integrated Molecular Characterization of PBL 37 1 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 12, 2017; DOI: 10.1158/0008-5472.CAN-17-2581 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 38 Corresponding Author 39 Junko Takita 40 Department of Pediatrics, 41 The University of Tokyo, 42 Hongo 7-3-1. Bunkyo-ku, 43 Tokyo, 113-8655 Japan 44 TEL: +81-3-3815-5411 (Ext. 33462) 45 FAX: +81-3-3816-4108 46 E-mail: [email protected] 47 48 Disclosure of Potential Conflicts of Interest 49 The authors declare no potential conflicts of interest. 50 51 Notes 52 Our manuscript contains 147 words of abstract, 5058 words of main text, 5 figures, no 53 tables, 10 supplementary figures, and 13 supplementary tables. 54 55 2 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 12, 2017; DOI: 10.1158/0008-5472.CAN-17-2581 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 56 Abstract 57 Pancreatoblastoma (PBL) is a rare pediatric pancreatic malignancy for which the 58 molecular pathogenesis is not understood. In this study, we report the findings of an 59 integrated multi-omics study of whole exome and RNA sequencing as well as 60 genome-wide copy number and methylation analyses of 10 PBL cases. The PBL genome 61 was characterized by a high frequency of aberrant activation of the Wnt signaling 62 pathway, either via somatic mutations of CTNNB1 (90%) and copy-neutral loss of 63 heterozygosity (CN-LOH) of APC (10%). In addition, imprinting dysregulation of IGF2 as a 64 consequence of CN-LOH (80%), gain of paternal allele (10%), and gain of methylation 65 (10%) were universally detected. At the transcriptome level, PBL exhibited an expression 66 profile characteristic of early pancreas progenitor-like cells along with upregulation of 67 the R-spondin/LGR5/RNF43 module. Our results offer a comprehensive description of the 68 molecular basis for PBL and highlight rational therapeutic targets for its treatment. 69 70 Introduction 71 Pancreatoblastoma (PBL) is a very rare pancreatic solid tumor that typically affects 72 young children, with a median age at diagnosis of 5 years. Including much less frequent 73 adult cases, PBL comprises less than 1% of all pancreatic non-endocrine tumors; despite 74 its rarity, it is the most common malignant pancreatic tumor in children younger than 10 75 years (1). Morphologically, PBL resembles fetal pancreatic tissue at gestational age of 8 76 weeks, manifesting multi-lineage elements with acinar, ductal and endocrine 77 differentiation, which suggests a primitive cellular origin of PBL (2). Owing to its rarity, 78 optimized therapeutic strategies, including targeted therapies, have not been 79 established for PBL; only the complete surgical resection is of proven prognostic value. 80 Thus, children with unresectable or relapsed disease still have a very poor prognosis (3), 81 which prompts a need for novel therapeutic modalities based on a better understanding 82 of its molecular pathogenesis. 83 Several case studies have revealed recurrent alterations affecting the Wnt/β-catenin 84 pathway genes, including APC and CTNNB1 (encoding β-catenin), and a loss of 85 heterozygosity (LOH) on chromosome 11p in a subset of sporadic PBL (4,5). 86 Correspondingly, PBL cases associated with familial adenomatous polyposis and 87 Beckwith-Wiedemann syndrome (BWS) have also been reported (4,6). By contrast, except 88 for only a few adult PBL cases exhibiting inactivation of SMAD4 (7), mutations affecting 89 KRAS, TP53, CDKN2A, and SMAD4, the four common targets of oncogenic events in 90 pancreatic ductal adenocarcinoma (PDAC), have not been reported in PBL (4). These 3 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 12, 2017; DOI: 10.1158/0008-5472.CAN-17-2581 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 91 clinicopathological and genetic features suggest a distinctive oncogenic mechanism of 92 this disease. However, because no comprehensive genomic studies have been reported 93 thus far, our knowledge about the molecular basis of PBL is still very limited. 94 In this study, we analyzed 16 primary or metastatic tumor specimens from 10 cases 95 with PBL using targeted deep sequencing of 155 cancer driver genes, whole exome 96 sequencing (WES), RNA sequencing, and genome-wide copy number and methylation 97 analyses. This multi-omics approach allowed us to obtain a comprehensive registry of the 98 molecular lesions underlying the pathogenesis of PBL. 99 100 Materials and Methods 101 Subjects and samples 102 This study comprised 16 tumor samples from 10 Japanese patients with PBL, among 103 which fresh frozen tumors were obtained from 6 patients, and for the remaining 4 104 patients, formalin-fixed paraffin-embedded (FFPE) samples were procured. Written 105 informed consent was obtained according to protocols approved by the Human Genome, 106 Gene Analysis Research Ethics Committee of the University of Tokyo, and other 107 participating institutes. Matched peripheral blood samples were obtained and used as 108 germline controls for WES and amplicon deep sequencing in 6 cases. For PBL001, a total 109 of 7 samples (one from the primary, two from the second, and four from the third 110 surgery) were included. The diagnosis of PBL was centrally reviewed and confirmed; 111 staging was done based on WHO classification. All patients underwent surgery with or 112 without chemotherapy and radiation therapy. One case (PBL001) had been treated for the 113 progressive disease with several different regimens, including temozolomide (TMZ), 114 between the first and second surgeries. See Supplementary Table S1 for clinical 115 characteristics and experimental design summary. 116 117 Targeted deep sequencing and mutation calling 118 For fresh frozen samples, sequencing libraries were constructed using a SureSelect-XT 119 kit (Agilent Technologies) according to the manufacturer’s protocol. For FFPE samples, a 120 KAPA Hyper Prep kit (Kapa Biosystems) was used with a modified protocol to utilize the 121 adapter and PCR primers of an Agilent SureSelect-XT kit. Target enrichment was 122 performed using a SureSelect custom bait library that we previously designed to 123 investigate gene mutations in gastrointestinal cancers (Inoue, et al., in preparation). The 124 bait library was designed to include all coding exons of 127 genes, hotspot regions
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