RT Journal
A1 Totoki, Yasushi
A1 Yoshida, Akihiko
A1 Hosoda, Fumie
A1 Nakamura, Hiromi
A1 Hama, Natsuko
A1 Ogura, Koichi
A1 Yoshida, Aki
A1 Fujiwara, Tomohiro
A1 Arai, Yasuhito
A1 Toguchida, Junya
A1 Tsuda, Hitoshi
A1 Miyano, Satoru
A1 Kawai, Akira
A1 Shibata, Tatsuhiro
T1 Unique mutation portraits and frequent COL2A1 gene alteration in chondrosarcoma
JF Genome Research 
JO Genome Research 
YR 2014 
FD July 14 
DO 10.1101/gr.160598.113 
SP gr.160598.113 
UL http://genome.cshlp.org/content/early/2014/07/14/gr.160598.113.abstract 
AB Chondrosarcoma is the second most frequent malignant bone tumor. However, the etiological background of chondrosarcomagenesis remains largely unknown, along with detailed information on molecular alterations, including potential therapeutic targets. Massively parallel paired-end sequencing of whole genomes of ten primary chondrosarcomas revealed that the process of accumulation of somatic mutations is homogeneous irrespective of pathological subtype or the presence of IDH1 mutation and 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 cohort, we identified somatic alterations of the COL2A1 gene, which encodes an essential extracellular matrix protein in chondro-skeletal 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. Under 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.