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From Hereditary Cancer Syndrome to Sporadic Cancer Etiology: Genetic Linkage of DMS-MFH to Chromosome 9p21-22 • 724

Diaphyseal Medullary Stenosis with Malignant Fibrous Histiocytoma (DMS-MFH) is an inherited autosomal dominant bone dysplasia and cancer syndrome of unknown etiology. The syndrome is characterized by cortical growth abnormalities, bone infarctions, pathologic fractures, progressive wasting and bowing of the lower extremities and a 35% risk of developing MFH. Sporadic MFH represents 6% of all bone sarcomas and is one of the few malignancies where previous osseous injury has been implicated in tumorigenesis. Since inherited and sporadic cancers are caused by the same genetic defect, a genetic linkage study was undertaken with three large, multi-generational DMS-MFH kindreds. A genome-wide search was performed using microsatellite markers from the Human Screening Set, V. 4. By two-point linkage analysis, a maximal LOD score of Z = 5.53 at ⊝ = 0.03 was obtained with marker D9S171. Haplotype analysis revealed three recombinant events, defining the DMS-MFH locus to a 3 cM region between markers D9S1778 and D9S171. This genetic position was localized to the cytogenetic region 9p21-22 - a cytogenetic region implicated in a variety of cancers, including bladder carcinoma, acute lymphoblastic leukemia and gliomas, and known to contain a number of cell-cycle and growth regulating genes. Next, MFH tumor DNA from a DMS-MFH patient was analyzed with microsatellite markers across the linked region. Loss of heterozygosity (LOH) in the patients normal chromosome was demonstrated through the entire DMS-MFH critical region. Finally, LOH analysis of sporadic MFH tumor and paired constitutive DNA revealed that 4/6 tumors had demonstrable 9p21-22 deletions. One of the samples was homozygously deleted across this region.