Near-Haploidy and Subsequent Polyploidization Characterize the Progression of Peripheral Chondrosarcoma

Abstract

Chondrosarcomas are malignant cartilaginous tumors arising centrally in bone (central chondrosarcoma), or secondarily within the cartilaginous cap of osteochondroma (peripheral chondrosarcoma). We previously used DNA flow cytometry to demonstrate that near-haploidy is relatively frequent in peripheral chondrosarcomas. We performed fluorescence in situ hybridization (FISH) to interphase nuclei using centromeric probes, a genome wide loss of heterozygosity (LOH) analysis, and comparative genomic hybridization on five peripheral chondrosarcomas. We demonstrated near-haploidy in two low-grade tumors with only one copy and LOH of most chromosomes. Few chromosomes are disomic, with retention of heterozygosity and overrepresentation at comparative genomic hybridization. One tumor contains both a near-haploid clone with chromosomes in monosomic and disomic state, and an exactly duplicated clone. Two high-grade tumors clearly demonstrate polyploidization because most chromosomes show LOH and two copies at FISH, whereas few chromosomes have four copies with retention of heterozygosity. Using DNA from a relative, we demonstrate that chromosome loss is random regardless of parental origin. Using FISH on paraffin slides, we exclude near-haploidy to result from meiosis-like division in binucleated cells, characteristic for chondrosarcoma. In conclusion, our results indicate that near-haploidy characterizes the progression from osteochondroma toward low-grade chondrosarcoma. Moreover, further progression toward high-grade chondrosarcoma is characterized by polyploidization. Chondrosarcoma, the second most common primary malignant bone tumor after osteosarcoma, is a malignant cartilage-forming tumor occurring predominantly in adults. The majority of chondrosarcomas develops de novo and is located centrally within the medullary cavity (central chondrosarcoma). In contrast, ϳ15% arise within the cartilage cap of a long-standing osteochondroma (peripheral chondrosarcoma), mostly in patients suffering from the hereditary multiple exostoses syndrome. Hereditary multiple exostoses syndrome is a familial disorder with an autosomal dominant mode of inheritance.1-4 Malignant transformation is estimated to occur in 1 to 5% of osteochondromas.The development of peripheral chondrosarcoma results in genetic instability characterized by a high percentage of loss of heterozygosity (LOH) and a wide variation in DNA ploidy.5 LOH in peripheral chondrosarcoma most frequently involves the TP53 (80%), RB1 (71%), and EXT1 (65%) loci. 5 In contrast, peridiploidy and a low percentage of LOH in central tumors indicates that a different oncogenic molecular mechanism may be operative. 5 We have detected hypodiploidy, which is uncommon for human solid tumors, in 29% of peripheral chondrosarcomas and not in central chondrosarcomas.5 Others mention hypodiploidy in 8 to 31% of chondrosarcomas without further subclassification.6 -9 Near-haploidy, which is a very rare phenomenon in human solid tumors in general, is found especially in low-grade peripheral chon...

Secondary peripheral chondrosarcoma evolving from osteochondroma as a result of outgrowth of cells with functional EXT

“…EXT1 or EXT2 acquire one or more additional genetic alterations to progress into malignancy (Bove´e et al, 2000). By analyzing clinically and radiologically well-documented peripheral cartilaginous tumors, we demonstrate that homozygous inactivation of the EXT1 locus in sporadic secondary peripheral chondrosarcoma (2/17, 12%) is much less frequently detected than expected based on the assumption that it originates in a sporadic osteochondroma, in which homozygous inactivation of EXT1 is found in B80% of the cases reported by our institution (Hameetman et al, 2007b;Reijnders et al, 2010).…”

Heterogeneous and Complex Rearrangements of Chromosome Arm 6q in Chondromyxoid Fibroma

“…gov/Chromosomes/ 2009). [23][24][25][26] Despite the extensive analyses performed, the mechanisms underlying the genesis of CMF remains elusive. A transcriptomic approach might be helpful, combining wide genome scale expression profiling and microRNA profiling with the observed genetic changes.…”

Epiphyseal growth plate and secondary peripheral chondrosarcoma: the neighbours matter

“…Additionally, IDH1/IDH2 mutations are shown not to be involved in secondary peripheral chondrosarcomas formation [76]. Malignant progression of secondary peripheral chondrosarcomas is characterized by a high percentage of loss of heterozygosity (ie CDKN2A/p16, TP53, RB1 ) and ploidy ranging from half to twice the normal DNA content [77][78][79]. It suggests that p16, p53 and RB1 are involved in neoplastic transformation of an osteochondroma.…”