COL2A1 Is Frequently Mutated in Chondrosarcoma

Chondrosarcoma is a type of malignant bone tumor derived from cartilage-producing cells. Little is known about the genetic features of chondrosarcoma other than the existence of recurring IDH1 and IDH2 mutations. To gain further insight into the molecular etiology of chondrosarcoma, Tarpey and colleagues performed whole-exome sequencing of 49 untreated chondrosarcomas and matched normal tissue. The second most frequently mutated gene after IDH1 and IDH2, which were collectively mutated in 59% (29/49) of tumors, was collagen, type II, alpha 1 (COL2A1), which was mutated in 37% (18/49) of chondrosarcomas. Interestingly, COL2A1 is highly expressed in normal chondrocytes and encodes the α chain of type II collagen, a major component of the articular cartilage found at the end of bones at joints. COL2A1 mutations were highly enriched in chondrosarcomas compared with other bone cancers and other collagen genes, indicating the specificity of COL2A1 mutations for this tumor type. Although a proportion of cases had a pattern of COL2A1 mutations that seemed compatible with a loss-of-function mechanism, immuno-histochemical analysis showed aberrant COL2A1 staining in the majority of chondrosarcomas, with abnormal focal COL2A1 staining more common than COL2A1 loss in COL2A1–mutant tumors. Of note, COL2A1 staining was also absent or focal in approximately half of COL2A1–wild-type chondrosarcomas tested, suggesting that type II collagen deposition may be disrupted in chondrosarcomas by additional mechanisms. Although in vivo studies are needed to confirm the role of COL2A1 in chondrosarcoma, these findings raise the possibility that production of abnormal type II collagen α chains may have dominant-negative effects upon collagen maturation and cartilage matrix deposition, which could disrupt chondrocyte differentiation and drive the development of chondrosarcoma.

Tarpey PS, Behjati S, Cooke SL, Van Loo P, Wedge DC, Pillay N, et al. Frequent mutation of the major cartilage collagen gene COL2A1 in chondrosarcoma. Nat Genet 2013 Jun 16 [Epub ahead of print].

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