Dataset Information

Frequent mutation of the major cartilage collagen gene COL2A1 in chondrosarcoma.

ABSTRACT: Chondrosarcoma is a heterogeneous collection of malignant bone tumors and is the second most common primary malignancy of bone after osteosarcoma. Recent work has identified frequent, recurrent mutations in IDH1 or IDH2 in nearly half of central chondrosarcomas. However, there has been little systematic genomic analysis of this tumor type, and, thus, the contribution of other genes is unclear. Here we report comprehensive genomic analyses of 49 individuals with chondrosarcoma (cases). We identified hypermutability of the major cartilage collagen gene COL2A1, with insertions, deletions and rearrangements identified in 37% of cases. The patterns of mutation were consistent with selection for variants likely to impair normal collagen biosynthesis. In addition, we identified mutations in IDH1 or IDH2 (59%), TP53 (20%), the RB1 pathway (33%) and Hedgehog signaling (18%).

SUBMITTER: Tarpey PS

PROVIDER: S-EPMC3743157 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Frequent mutation of the major cartilage collagen gene COL2A1 in chondrosarcoma.

Tarpey Patrick S PS Behjati Sam S Cooke Susanna L SL Van Loo Peter P Wedge David C DC Pillay Nischalan N Marshall John J O'Meara Sarah S Davies Helen H Nik-Zainal Serena S Beare David D Butler Adam A Gamble John J Hardy Claire C Hinton Jonathon J Jia Ming Ming MM Jayakumar Alagu A Jones David D Latimer Calli C Maddison Mark M Martin Sancha S McLaren Stuart S Menzies Andrew A Mudie Laura L Raine Keiran K Teague Jon W JW Tubio Jose M C JM Halai Dina D Tirabosco Roberto R Amary Fernanda F Campbell Peter J PJ Stratton Michael R MR Flanagan Adrienne M AM Futreal P Andrew PA

Nature genetics 20130616 8

Chondrosarcoma is a heterogeneous collection of malignant bone tumors and is the second most common primary malignancy of bone after osteosarcoma. Recent work has identified frequent, recurrent mutations in IDH1 or IDH2 in nearly half of central chondrosarcomas. However, there has been little systematic genomic analysis of this tumor type, and, thus, the contribution of other genes is unclear. Here we report comprehensive genomic analyses of 49 individuals with chondrosarcoma (cases). We identif ...[more]

PMID: 23770606

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Project description:One of the factors preventing clinical application of regenerative medicine to degenerative cartilage diseases is a suitable source of cells. Chondrocytes, the only cell type of cartilage, grown in vitro under culture conditions to expand cell numbers lose their phenotype along with the ability to generate hyaline cartilaginous tissue. In this study we determine that a serum- and growth-factor-free three-dimensional (3D) culture system restores the ability of the passaged chondrocytes to form cartilage tissue in vitro, a process that involves sox9.Bovine articular chondrocytes were passaged twice to allow for cell number expansion (P2) and cultured at high density on 3D collagen-type-II-coated membranes in high glucose content media supplemented with insulin and dexamethasone (SF3D). The cells were characterized after monolayer expansion and following 3D culture by flow cytometry, gene expression, and histology. The early changes in signaling transduction pathways during redifferentiation were characterized.The P2 cells showed a progenitor-like antigen profile of 99% CD44(+) and 40% CD105(+) and a gene expression profile suggestive of interzone cells. P2 in SF3D expressed chondrogenic genes and accumulated extracellular matrix. Downregulating insulin receptor (IR) with HNMPA-(AM3) or the PI-3/AKT kinase pathway (activated by insulin treatment) with Wortmannin inhibited collagen synthesis. HNMPA-(AM3) reduced expression of Col2, Col11, and IR genes as well as Sox6 and -9. Co-immunoprecipitation and chromatin immunoprecipitation analyses of HNMPA-(AM3)-treated cells showed binding of the coactivators Sox6 and Med12 with Sox9 but reduced Sox9-Col2a1 binding.We describe a novel culture method that allows for increase in the number of chondrocytes and promotes hyaline-like cartilage tissue formation in part by insulin-mediated Sox9-Col2a1 binding. The suitability of the tissue generated via this approach for use in joint repair needs to be examined in vivo.

Dataset Information

Frequent mutation of the major cartilage collagen gene COL2A1 in chondrosarcoma.

Publications

Frequent mutation of the major cartilage collagen gene COL2A1 in chondrosarcoma.

Similar Datasets

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