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 () and Junko Takita ()
Additional contact information
Masafumi Seki: Graduate School of Medicine, The University of Tokyo
Riki Nishimura: Graduate School of Medicine, The University of Tokyo
Kenichi Yoshida: Graduate School of Medicine, Kyoto University
Teppei Shimamura: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo
Yuichi Shiraishi: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo
Yusuke Sato: Graduate School of Medicine, Kyoto University
Motohiro Kato: Graduate School of Medicine, The University of Tokyo
Kenichi Chiba: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo
Hiroko Tanaka: Laboratory of Sequence Data Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo
Noriko Hoshino: Graduate School of Medicine, The University of Tokyo
Genta Nagae: Research Center for Advanced Science and Technology, The University of Tokyo
Yusuke Shiozawa: Graduate School of Medicine, Kyoto University
Yusuke Okuno: Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo
Hajime Hosoi: Kyoto Prefectural University of Medicine, Graduate School of Medical Science
Yukichi Tanaka: Kanagawa Children's Medical Center
Hajime Okita: Molecular Pathology Laboratory, National Research Institute for Child Health and Development
Mitsuru Miyachi: Kyoto Prefectural University of Medicine, Graduate School of Medical Science
Ryota Souzaki: Reproductive and Developmental Medicine, Faculty of Medical Sciences, Kyushu University
Tomoaki Taguchi: Reproductive and Developmental Medicine, Faculty of Medical Sciences, Kyushu University
Katsuyoshi Koh: Saitama Children’s Medical Center
Ryoji Hanada: Saitama Children’s Medical Center
Keisuke Kato: Ibaraki Children’s Hospital
Yuko Nomura: School of Medicine, Fukuoka University
Masaharu Akiyama: The Jikei University School of Medicine
Akira Oka: Graduate School of Medicine, The University of Tokyo
Takashi Igarashi: Graduate School of Medicine, The University of Tokyo
Satoru Miyano: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo
Hiroyuki Aburatani: Research Center for Advanced Science and Technology, The University of Tokyo
Yasuhide Hayashi: Gunma Children's Medical Center
Seishi Ogawa: Graduate School of Medicine, Kyoto University
Junko Takita: Graduate School of Medicine, The University of Tokyo

Nature Communications, 2015, vol. 6, issue 1, 1-8

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8557

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