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

Integrated genetic and epigenetic analysis defines novel molecular subgroups in rhabdomyosarcoma.

Author information

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.

PMID:
26138366
PMCID:
PMC4506514
DOI:
10.1038/ncomms8557
[Indexed for MEDLINE]
Free PMC Article

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