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 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.