HEREDITARY MULTIPLE EXOSTOSIS AND CHONDROSARCOMA - LINKAGE TO CHROMOSOME-11 AND LOSS OF HETEROZYGOSITY FOR EXT-LINKED MARKERS ON CHROMOSOME-11 AND CHROMOSOME-8

Hereditary multiple exostosis (EXT) is an autosomal dominant disorder characterized by bony exostoses at the ends of the long bones. Linkage studies have recently suggested that there are three chromosomal loca tions for EXT genes, 8q24.1 (EXT1), the pericentric region of 11 (EXT2 ), and 19p (EXT3). As part of a larger study to determine the frequenc ies of the three EXT types in the United States, we have ascertained a large multigenerational family with EXT and one family member with a chondrosarcoma. This family demonstrated linkage of the disease to chr omosome 11 markers. The constitutional and tumor DNAs from the affecte d family member were compared using short-tandem-repeat markers from c hromosomes 8, 11, and 19. Loss of heterozygosity (LOH) in the tumor wa s observed for chromosome 8 and 11 markers, but chromosome 19 markers were intact. An apparent deletion of the marker D11S303 was observed i n constitutional DNA from all affected individuals and in the tumor sa mple. These results indicate that the EXT2 gene maps to the region con taining marker D11S903, which is flanked by markers D11S1355 and D11S1 361. Additional constitutional and chondrosarcoma DNA pairs from six u nrelated individuals, two of whom had EXT, were similarly analyzed. On e tumor from an individual with EXT demonstrated LOH for chromosome 8 markers, and a person with a sporadic chondrosarcoma was found to have tumor-specific LOH and a homozygous deletion of chromosome 11 markers . These findings suggest that EXT genes may be tumor-suppressor genes and that the initiation of tumor development may follow a multistep mo del.