GENETICS OF PEDIATRIC RHABDOID TUMORS

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Rhabdoid tumor is a rapidly fatal malignancy which generally presents in the first two years of life. The tumors may present in various locations of the body, but are most often seen in the brain and Kidney. Some patients have been reported with both a primary central nervous system malignancy and a primary renal rhabdoid tumor, suggesting that the tumors have a common molecular etiology. We have reported that rhabdoid tumor of the brain, or a variant of rhabdoid tumor referred to as a atypical teratoid tumor, is characterized by monosomy or deletion of chromosome 22. Combined cytogenetic and molecular studies have been used to define a critical region in 22q11.2 which we proposed contains a rhabdoid tumor locus. We hypothesize that homozygous deletion or inactivation of a tumor suppressor gene within this region is responsible for the development of pediatric rhabdoid tumors of the central nervous system kidney, and extra-renal tissues. The minimal critical region for this locus is less than 500 kb, and spans the region between the immunoglobulin loci and the BCR gene. We have constructed a contiguous overlapping set of cosmids and bacterial artificial chromosomes (BACs) which spans the rhabdoid tumor critical region. The cosmids and BACs will be used to isolate candidate cDNAs for the rhabdoid tumor gene by a combination of large scale genomic sequence analysis and exon trapping methods. Candidate genes will then be analyzed for genomic alterations and mutations in matched m=normal and tumor tissue from patients with rhabdoid tumors. We will determine the genomic structure of the gene, and analyze its expression in normal and tumor tissues. Identification of the rhabdoid tumor gene will be a major contribution towards the design of sensitive diagnostic assays, and improved treatment protocols.