Loss of heterozygosity and DNA ploidy point to a diverging genetic mechanism in the origin of peripheral and central chondrosarcoma

Abstract

Chondrosarcomas are malignant cartilaginous tumors arising centrally in bone (central chondrosarcoma), or secondarily within the cartilaginous cap of a hereditary or sporadic exostosis (peripheral chondrosarcoma). Loss of heterozygosity (LOH) was studied by microsatellite analysis at the loci harboring the EXT genes (implicated in hereditary multiple exostoses), the EXT-like genes, and at 9p21, 13q14, 17p13, and chromosome 10. Nineteen of 20 peripheral chondrosarcomas showed LOH at all loci tested, while only 3 of 12 central chondrosarcomas exhibited LOH, restricted to 9p21, 10, 13q14, and 17p13. LOH at 9p21 did not appear to involve the CDKN2A gene, as assessed by SSCP analysis. DNA flow cytometry demonstrated a wide variation in the ploidy status in peripheral chondrosarcomas (DNA indexes, 0.56-2.01), whereas central chondrosarcomas were predominantly peridiploid. Near-haploidy found in peripheral chondrosarcomas could explain part of the high LOH percentages. Ki-67 immunohistochemistry suggested a higher proliferation rate in peripheral chondrosarcomas. Our results indicate that peripheral chondrosarcomas, arising secondarily to an exostosis, may obtain genetic alterations during malignant transformation, with subsequent genetic instability as demonstrated by a high percentage of LOH and a wide variation in ploidy status. In contrast, peridiploidy and a low percentage of LOH in central tumors suggest that a different oncogenic molecular mechanism may be operative.

A distinct phenotype characterizes tumors from a putative genetic trait involving chondrosarcoma and breast cancer occurring in the same patient

“…This finding is remarkable because within the general population 15% of all chondrosarcomas are peripherally localized, suggesting a specific genetic mechanism in the development of these breast cancer-associated cartilaginous tumors. This hypothesis is corroborated by Bovee et al, 11 who described that different genetic mechanisms are operational in central and peripheral chondrosarcomas. No correlation could be made with histological grade, because of the relatively small numbers of mostly low-grade chondrosarcomas.…”

“…[6][7][8][9] Recent data have shown that both subtypes are likely to originate due to different genetic mechanisms. [10][11][12] Secondary chondrosarcomas often have near-haploidy in low-grade and polyploidization in high-grade peripheral tumors. In contrast, central chondrosarcomas show few genetic aberrations.…”

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

“…Seventeen sporadic peripheral chondrosarcomas, well-known for not showing point mutations in the EXT genes (Bove´e et al, 1999;Hallor et al, 2009;Zuntini et al, 2010), were collected to study DNA copy-number alterations by using a custom-made Agilent oligonucleotide-based microarray containing 44 000 probes with a tiling coverage of EXT1/2 genes and additional 68 genes involved in heparan and chondroitin sulfate biosynthesis as described by Szuhai et al (2011). Only alterations of EXT genes were investigated.…”

“…Secondary peripheral chondrosarcomas are malignant cartilage-producing tumors. Contrary to what is observed in osteochondromas, homozygous inactivations of the EXT genes are detected in a much smaller subset (B15%) of secondary peripheral chondrosarcomas (Hecht et al, 1995;Raskind et al, 1995;Bove´e et al, 1999;Hallor et al, 2009;Zuntini et al, 2010).…”

Primary cilia organization reflects polarity in the growth plate and implies loss of polarity and mosaicism in osteochondroma

“…24 Immunohistochemistry was performed for proliferation rate analysis using a monoclonal antibody against Ki-67 (clone MIB1, 1:100; Dako, Glostrup, Germany) according to standard laboratory procedures. 25 …”