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. Genes Chromosomes Cancer 26:237–246, 1999. © 1999 Wiley‐Liss, Inc.

High-Throughput Screening of Myxoid Liposarcoma Cell Lines: Survivin Is Essential for Tumor Growth

“…Both nuclear and cytoplasmic expression was scored separately by two independent observers (J.V.M.G.B., M.A.G.). A semiquantitative scoring system was used, combining the staining intensity (0 = negative, 1 = weak, 2 = moderate, 3 = strong) and the percentage of positive tumor cells (0 = 0%, 1 = 1%-25%, 2 = 25%-50%, 3 = 51%-75%, and 4 = 76%-100%) as described previously [22].…”

Molecular pathology of sarcomas: concepts and clinical implications

“…These encode glycosyltransferases catalyzing heparan sulphate chain elongation on heparan sulphate proteoglycans, which are important for cellular signaling of Hedgehog, Fibroblast Growth Factor, Wnt, Bone Morphogenetic Protein and Transforming Growth Factor beta. Thus, while it is clear that inactivation of EXT underlies osteochondroma development [28, 29], so far, unidentified additional genetic changes are required for malignant transformation towards secondary peripheral chondrosarcoma, resulting in more complex karyotypes including near-haploidy and polyploidization [30, 31]. In contrast, in the more common central chondrosarcoma EXT is not involved [32].…”

Multiple Osteochondromas: Clinicopathological and Genetic Spectrum and Suggestions for Clinical Management

“…The process of malignant transformation is genetically represented by chromosomal instability [95], probably caused by defects in spindle formation. The LOH found in osteochondroma was restricted to 8q24 [31], whereas in secondary peripheral chondrosarcomas LOH was found in virtually all loci tested [95].…”

“…The LOH found in osteochondroma was restricted to 8q24 [31], whereas in secondary peripheral chondrosarcomas LOH was found in virtually all loci tested [95]. Also a broad range in DNA ploidy including near-haploidy and non-specific chromosomal alterations were found [95,96].…”

“…The LOH found in osteochondroma was restricted to 8q24 [31], whereas in secondary peripheral chondrosarcomas LOH was found in virtually all loci tested [95]. Also a broad range in DNA ploidy including near-haploidy and non-specific chromosomal alterations were found [95,96]. DNA-flow cytometry of the cartilaginous cap of osteochondromas showed mild aneuploidy [31], whereas more severe aneuploidy [97-99], including near-haploidy [95], was seen in grade I secondary peripheral chondrosarcomas.…”