Integrated genetic and epigenetic analysis defines novel molecular subgroups in rhabdomyosarcoma

Masafumi Seki; Riki Nishimura; Kenichi Yoshida; Teppei Shimamura; Yuichi Shiraishi; Yusuke Sato; Motohiro Kato; Kenichi Chiba; Hiroko Tanaka; Noriko Hoshino; Genta Nagae; Yusuke Shiozawa; Yusuke Okuno; Hajime Hosoi; Yukichi Tanaka; Hajime Okita; Mitsuru Miyachi; Ryota Souzaki; Tomoaki Taguchi; Katsuyoshi Koh; Ryoji Hanada; Keisuke Kato; Yuko Nomura; Masaharu Akiyama; Akira Oka; Takashi Igarashi; Satoru Miyano; Hiroyuki Aburatani; Yasuhide Hayashi; Seishi Ogawa; Junko Takita

doi:10.1038/ncomms8557

Integrated genetic and epigenetic analysis defines novel molecular subgroups in rhabdomyosarcoma

Nat Commun. 2015 Jul 3:6:7557. doi: 10.1038/ncomms8557.

Authors

Masafumi Seki¹, Riki Nishimura¹, Kenichi Yoshida², Teppei Shimamura³, Yuichi Shiraishi⁴, Yusuke Sato², Motohiro Kato⁵, Kenichi Chiba⁴, Hiroko Tanaka⁶, Noriko Hoshino⁷, Genta Nagae⁸, Yusuke Shiozawa², Yusuke Okuno⁹, Hajime Hosoi¹⁰, Yukichi Tanaka¹¹, Hajime Okita¹², Mitsuru Miyachi¹⁰, Ryota Souzaki¹³, Tomoaki Taguchi¹³, Katsuyoshi Koh¹⁴, Ryoji Hanada¹⁴, Keisuke Kato¹⁵, Yuko Nomura¹⁶, Masaharu Akiyama¹⁷, Akira Oka¹, Takashi Igarashi¹⁸, Satoru Miyano¹⁹, Hiroyuki Aburatani⁸, Yasuhide Hayashi²⁰, Seishi Ogawa², Junko Takita¹

Affiliations

¹ Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
² 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.
³ 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.
⁴ Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
⁵ 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.
⁶ Laboratory of Sequence Data Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
⁷ Department of Pediatric Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.
⁸ Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo 153-8904, Japan.
⁹ 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.
¹⁰ Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto 602-8566, Japan.
¹¹ Department of Pathology, Kanagawa Children's Medical Center, Yokohama 232-8555, Japan.
¹² Molecular Pathology Laboratory, Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan.
¹³ Department of Pediatric Surgery, Reproductive and Developmental Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
¹⁴ Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama 339-8551, Japan.
¹⁵ Division of Pediatric Hematology and Oncology, Ibaraki Children's Hospital, Mito 311-4145, Japan.
¹⁶ Department of Pediatrics, School of Medicine, Fukuoka University, Fukuoka 814-0180, Japan.
¹⁷ Department of Pediatrics, The Jikei University School of Medicine, Tokyo 105-8471, Japan.
¹⁸ 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.
¹⁹ 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.
²⁰ Department of Hematology/Oncology, Gunma Children's Medical Center, Shibukawa, Gunma, 377-8577, Japan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Cell Cycle Proteins / genetics
Child
Child, Preschool
DNA Methylation / genetics
Epigenesis, Genetic / genetics*
Exome
F-Box Proteins / genetics
F-Box-WD Repeat-Containing Protein 7
Female
Forkhead Box Protein O1
Forkhead Transcription Factors / genetics
Gene Expression Regulation, Neoplastic / genetics*
Humans
Infant
Male
Mutation
PAX3 Transcription Factor
PAX7 Transcription Factor / genetics
PTEN Phosphohydrolase / genetics
Paired Box Transcription Factors / genetics
Prognosis
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins c-akt / genetics
RNA, Messenger / metabolism*
Receptor, Fibroblast Growth Factor, Type 4 / genetics
Repressor Proteins / genetics
Rhabdomyosarcoma / classification
Rhabdomyosarcoma / genetics
Rhabdomyosarcoma, Alveolar / classification
Rhabdomyosarcoma, Alveolar / genetics*
Rhabdomyosarcoma, Embryonal / classification
Rhabdomyosarcoma, Embryonal / genetics*
Transcriptome
Tumor Suppressor Protein p53 / genetics
Ubiquitin-Protein Ligases / genetics
Young Adult
beta Catenin / genetics
ras Proteins / genetics

Substances

BCOR protein, human
CTNNB1 protein, human
Cell Cycle Proteins
F-Box Proteins
F-Box-WD Repeat-Containing Protein 7
FBXW7 protein, human
FOXO1 protein, human
Forkhead Box Protein O1
Forkhead Transcription Factors
PAX3 Transcription Factor
PAX3 protein, human
PAX7 Transcription Factor
PAX7 protein, human
Paired Box Transcription Factors
Proto-Oncogene Proteins
RNA, Messenger
Repressor Proteins
TP53 protein, human
Tumor Suppressor Protein p53
beta Catenin
Ubiquitin-Protein Ligases
FGFR4 protein, human
Receptor, Fibroblast Growth Factor, Type 4
Proto-Oncogene Proteins c-akt
PTEN Phosphohydrolase
PTEN protein, human
ras Proteins

Associated data

GEO/GSE41263
GEO/GSE63891