title: Integrated genetic and epigenetic analysis defines novel molecular subgroups in rhabdomyosarcoma.
abstract: Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in childhood. Here we studied 60 RMSs using whole-exome/-transcriptome sequencing, copy number (CN) and DNA methylome analyses to unravel the genetic/epigenetic basis of RMS. On the basis of methylation patterns, RMS is clustered into four distinct subtypes, which exhibits remarkable correlation with mutation/CN profiles, histological phenotypes and clinical behaviours. A1 and A2 subtypes, especially A1, largely correspond to alveolar histology with frequent PAX3/7 fusions and alterations in cell cycle regulators. In contrast, mostly showing embryonal histology, both E1 and E2 subtypes are characterized by high frequency of CN alterations and/or allelic imbalances, FGFR4/RAS/AKT pathway mutations and PTEN mutations/methylation and in E2, also by p53 inactivation. Despite the better prognosis of embryonal RMS, patients in the E2 are likely to have a poor prognosis. Our results highlight the close relationships of the methylation status and gene mutations with the biological behaviour in RMS.
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Seki
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Riki
authors.initials: R
authors.lastname: Nishimura
authors.affiliation: 1] Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan [2] Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: 1] Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan [2] Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Teppei
authors.initials: T
authors.lastname: Shimamura
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shiraishi
authors.affiliation: 1] Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan [2] Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sato
authors.affiliation: 1] Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan [2] Department of Cell Therapy and Transplantation Medicine, The University of Tokyo, Tokyo 113-8655, Japan [3] Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama 339-8551, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Kato
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Chiba
authors.affiliation: Laboratory of Sequence Data Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Department of Pediatric Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Hoshino
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo 153-8904, Japan.
authors.forename: Genta
authors.initials: G
authors.lastname: Nagae
authors.affiliation: 1] Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan [2] Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Shiozawa
authors.affiliation: 1] Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan [2] Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Yusuke
authors.identifier: 0000000331399272
authors.initials: Y
authors.lastname: Okuno
authors.affiliation: Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto 602-8566, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Hosoi
authors.affiliation: Department of Pathology, Kanagawa Children's Medical Center, Yokohama 232-8555, Japan.
authors.forename: Yukichi
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Molecular Pathology Laboratory, Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Okita
authors.affiliation: Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto 602-8566, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Miyachi
authors.affiliation: Department of Pediatric Surgery, Reproductive and Developmental Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Souzaki
authors.affiliation: Department of Pediatric Surgery, Reproductive and Developmental Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Taguchi
authors.affiliation: Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama 339-8551, Japan.
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Koh
authors.affiliation: Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama 339-8551, Japan.
authors.forename: Ryoji
authors.initials: R
authors.lastname: Hanada
authors.affiliation: Division of Pediatric Hematology and Oncology, Ibaraki Children's Hospital, Mito 311-4145, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kato
authors.affiliation: Department of Pediatrics, School of Medicine, Fukuoka University, Fukuoka 814-0180, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Nomura
authors.affiliation: Department of Pediatrics, The Jikei University School of Medicine, Tokyo 105-8471, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Akiyama
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Oka
authors.affiliation: 1] Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan [2] National Center for Child Health and Development, Tokyo 157-8535, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Igarashi
authors.affiliation: 1] Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan [2] Laboratory of Sequence Data Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo 153-8904, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.affiliation: Department of Hematology/Oncology, Gunma Children's Medical Center, Shibukawa, Gunma, 377-8577, Japan.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Hayashi
authors.affiliation: 1] Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan [2] Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Takita
mesh_terms: D000293:Adolescent; D018797:Cell Cycle Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D059472:Exome; D044783:F-Box Proteins / Q000235:genetics; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D000072041:PAX3 Transcription Factor; D051763:PAX7 Transcription Factor / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics; D051761:Paired Box Transcription Factors / Q000235:genetics; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism*; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D012208:Rhabdomyosarcoma / Q000145:classification / Q000235:genetics; D018232:Rhabdomyosarcoma, Alveolar / Q000145:classification / Q000235:genetics*; D018233:Rhabdomyosarcoma, Embryonal / Q000145:classification / Q000235:genetics*; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D055815:Young Adult; D051176:beta Catenin / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: C411984:BCOR protein, human; C495270:CTNNB1 protein, human; D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051763:PAX7 Transcription Factor; C497321:PAX7 protein, human; D051761:Paired Box Transcription Factors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D044767:Ubiquitin-Protein Ligases; C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D018631:ras Proteins