Frequent mutation of the major cartilage collagen gene COL2A1 in chondrosarcoma

Abstract

Chondrosarcoma (CHS) is a heterogeneous collection of malignant bone tumours and is the second most common primary malignancy of bone after osteosarcoma. Recent work has identified frequent, recurrent mutations in IDH1/2 in nearly half of central CHS. However, there has been little systematic genomic analysis of this tumour type and thus the contribution of other genes is unclear. Here we report comprehensive genomic analyses of 49 cases of CHS. We identified hypermutability of the major cartilage collagen 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 IDH1/2 (59%), TP53 (20%), the RB1 pathway (33%) and hedgehog signaling (18%).

Mutant IDH is sufficient to initiate enchondromatosis in mice

“…Because IDH mutations are present in both enchondromas and chondrosarcomas and expression of mutant Idh in mice results in the development of enchondroma-like lesions, not chondrosarcomas, it is likely that the mutation is causative for the benign precursor lesion, and additional mutations are needed for malignant progression. This notion is supported by the overall low frequency of genes harboring mutations in chondrosarcomas (33). This finding is consistent with previous data from mice overexpressing the Gli2 transcription factor, which develop enchondroma-like lesions but when crossed with mice deficient in p53, develop chondrosarcomas (34).…”

Analysis of PD-L1, T-cell infiltrate and HLA expression in chondrosarcoma indicates potential for response to immunotherapy specifically in the dedifferentiated subtype

“…Depending on the tumor type, some data suggest that PD-L1 expression on pretreatment specimens is associated with higher response rates. 9,16 However, the use of various PD-L1 clones with different detection methods and interpretation makes literature confusing and challenging to draw conclusions. In sarcoma patients, for instance, different expression patterns of PD-L1 are observed in soft-tissue sarcomas when comparing two studies.…”

“…Our results are in line with the fact that additional genetic changes occur in the anaplastic component of dedifferentiated chondrosarcoma, which may lead to higher numbers of mutations in this part of the tumor and thus occurrence of neoantigens. 16,28 We have learned from epithelial malignancies that tumors with high mutational load show strong T-cell responses and appear to be particularly sensitive to immunotherapy, such as immune checkpoint blockade. 29 This was also shown in animal models of osteosarcoma, a sarcoma known for its high genomic instability.…”

“…[13][14][15] Whole-exome sequencing of 49 chondrosarcomas identified a median of 22 non-synonymous mutations per tumor (range 1-93). 16 Grade II, grade III and dedifferentiated chondrosarcomas were significantly associated with a higher mutation burden, which can indicate a potential sensitivity to immune checkpoint blockade. Another reported predictive factor for response to anti PD-1 agents is PD-L1 expression before treatment, but this remains a matter of debate owing to the dynamic process of PD-L1 expression, the multiplicity of detection methods and the use of different cutoff values.…”

Insights into cancer biology through next-generation sequencing

“…10 Additionally, the affordability of sequencing today has resulted in more cancers being sequenced per experiment. Thus, rare lowfrequency cancer genes present in common cancers, 10-18 as well as common cancer genes present in rare cancers, 19,20 are also increasingly being identified. These forays into identification of cancer genes demonstrates one startling point: that an enormous amount of intertumour heterogeneity exists.…”