Malignant fibrous histiocytoma (MFH) is the most common adult soft tissue sarcoma and represents 6% of all bone cancers. No MFH inducing genes have been identified and previous molecular and cytogenetic investigations have failed to define any MFH gene loci. Diaphyseal Medullary Stenosis with Malignant Fibrous Histiocytoma (DMS-MFH; OMIM #112250) is an autosomal dominant bone dysplasia/bone cancer syndrome of unknown etiology wherein all affecteds develop distinct skeletal abnormalities and, most notably, 35% of affecteds develop bone MFH. A genome scan for the DMS-MFH gene locus in three unrelated DMS-MFH families linked the syndrome to an approximately 3 cM region on chromosome 9p21-22 with a maximal two-point lod score of 5.53 (marker D9S171 at 0 = 0.03). Interestingly, this region had previously been shown to be the site of chromosomal abnormalities in several other malignancies and contains a number of genes whose protein products are involved in growth regulation. To determine the genetic relationship between familial and sporadic forms of MFH, we examined sporadic and inherited tumor samples for loss of heterozygosity (LOH) in the DMSM-FH critical region. Paired bone (n=6) and soft tissue (n=26) sporadic MFH samples as well as one bone MFH from a DMS-MFH patient were analyzed using fluorescent microsatellite markers across chromosome 9p. Of the 30 informative samples, 6 of 7 bone (86%) and 10 of 22 soft tissue (45%) samples displayed LOH for at least one marker within the DMS-MFH critical region. Importantly, the alleles lost in the DMS-MFH tumor sample were from the non-affected chromosome, in accord with Knudson's "two-hit" theory. Furthermore, the LOH data effectively narrowed the DMS-MFH gene locus to < 2 cM by defining a minimal region of deletion common to MFH tumors. These findings support the hypothesis that a common genetic etiology underlies the rare familial and vastly more common non-familial forms of this particularly malignant sarcoma and provide the first consistent analysis on the molecular origin of MFH. Furthermore, the LOH data are consistent with the DMS-MFH gene encoding a tumor suppressor protein.

Original languageEnglish
Pages (from-to)176A
JournalJournal of Investigative Medicine
Issue number2
StatePublished - Feb 1999


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