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

Chondrosarcomas are malignant cartilaginous tumors arising centrally in bon e (central chondrosarcoma), or secondarily within the cartilaginous cap of a hereditary or sporadic exostosis (peripheral chondrosarcoma). Loss of het erozygosity (LOH) was studied by microsatellite analysis at the loci harbor ing the EXT genes (implicated in hereditary multiple exostoses), the OCT-li ke genes, and at 9p21, 13q14, 17p13, and chromosome 10. Nineteen of 20 peri pheral chondrosarcomas showed LOH at all loci tested, while only 3 of 12 ce ntral chondrosarcomas exhibited LOH, restricted to 9p21, 10, 13q14, and 17p 13. LOH at 9p21 did not appear to involve the CDKN2A gene, as assessed by S SCP analysis. DNA flow cytometry demonstrated a wide variation in the ploid y status in peripheral chondrosarcomas (DNA indexes, 0.56-2.01), whereas ce ntral chondrosarcomas were predominantly peridiploid. Near-haploidy found i n peripheral chondrosarcomas could explain part of the high LOH percentages . Ki-67 immunohistochemistry suggested a higher proliferation rate in perip heral chondrosarcomas. Our results indicate that peripheral chondrosarcomas , arising secondarily to an exostosis, may obtain genetic alterations durin g malignant transformation, with subsequent genetic instability as demonstr ated 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 sugges t that a different oncogenic molecular mechanism may be operative. Genes Ch romosomes Cancer 26:237-246, 1999. (C) 1999 Wiley-Liss, Inc.