title: Unique mutation portraits and frequent COL2A1 gene alteration in chondrosarcoma.
abstract: Chondrosarcoma is the second most frequent malignant bone tumor. However, the etiological background of chondrosarcomagenesis remains largely unknown, along with details on molecular alterations and potential therapeutic targets. Massively parallel paired-end sequencing of whole genomes of 10 primary chondrosarcomas revealed that the process of accumulation of somatic mutations is homogeneous irrespective of the pathological subtype or the presence of IDH1 mutations, is unique among a range of cancer types, and shares significant commonalities with that of prostate cancer. Clusters of structural alterations localized within a single chromosome were observed in four cases. Combined with targeted resequencing of additional cartilaginous tumor cohorts, we identified somatic alterations of the COL2A1 gene, which encodes an essential extracellular matrix protein in chondroskeletal development, in 19.3% of chondrosarcoma and 31.7% of enchondroma cases. Epigenetic regulators (IDH1 and YEATS2) and an activin/BMP signal component (ACVR2A) were recurrently altered. Furthermore, a novel FN1-ACVR2A fusion transcript was observed in both chondrosarcoma and osteochondromatosis cases. With the characteristic accumulative process of somatic changes as a background, molecular defects in chondrogenesis and aberrant epigenetic control are primarily causative of both benign and malignant cartilaginous tumors.
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, 104-0045, Japan;
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Totoki
authors.affiliation: Division of Pathology and Clinical Laboratories.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshida
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, 104-0045, Japan;
authors.forename: Fumie
authors.initials: F
authors.lastname: Hosoda
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, 104-0045, Japan;
authors.forename: Hiromi
authors.initials: H
authors.lastname: Nakamura
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, 104-0045, Japan;
authors.forename: Natsuko
authors.initials: N
authors.lastname: Hama
authors.affiliation: Division of Musculoskeletal Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, 104-0045, Japan;
authors.forename: Koichi
authors.initials: K
authors.lastname: Ogura
authors.affiliation: Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan;
authors.forename: Aki
authors.initials: A
authors.lastname: Yoshida
authors.affiliation: Division of Musculoskeletal Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, 104-0045, Japan;
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Fujiwara
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, 104-0045, Japan;
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Arai
authors.affiliation: Department of Tissue Regeneration, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan;
authors.forename: Junya
authors.initials: J
authors.lastname: Toguchida
authors.affiliation: Division of Pathology and Clinical Laboratories.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Tsuda
authors.affiliation: Laboratory of DNA Informatics Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, 108-8639, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Division of Musculoskeletal Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, 104-0045, Japan;
authors.forename: Akira
authors.initials: A
authors.lastname: Kawai
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, 104-0045, Japan; tashibat@ncc.go.jp.
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Shibata
mesh_terms: D030301:Activin Receptors, Type II / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002813:Chondrosarcoma / Q000235:genetics*; D024043:Collagen Type II / Q000235:genetics*; D005260:Female; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018216:Osteochondromatosis / Q000235:genetics*; D059467:Transcriptome
chemical_list: C499177:COL2A1 protein, human; D024043:Collagen Type II; C067625:FN1 protein, human; D005353:Fibronectins; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D030301:Activin Receptors, Type II; C425585:activin receptor type II-A