Identification of novel regions of deletion in familial Wilms' tumor by comparative genomic hybridization.

Wilms' tumor, an embryonic renal neoplasm diagnosed primarily in young children, can occur in either a noninheritable (sporadic) or a familial form, with the latter presenting earlier and more often at bilateral sites. Although familial Wilms' tumor is thought to develop through inherited and acquired mutational inactivation of the two alleles of predisposing tumor suppressor genes, only a small percentage of cases can be accounted for by mutations affecting the WT1 gene or linkage to the Beckwith-Weidemann syndrome of the BWS region on the short arm of chromosome 11. To find chromosomal regions that might contain genes important in the development of this disease, we used comparative genomic hybridization to analyze tumor specimens from familial cases for chromosomal regions that were consistently lost. Although inherited lesions of tumor suppressors are most often inactivating point mutations, accompanying somatic lesions in the malignant clones are often chromosomal deletions; therefore, consensus regions of loss in familial tumors are likely to harbor genes linked to familial predisposition. There were extensive genomic aberrations among the eight familial cases studied, with an average of 6.5 changes/tumor (range, 0-22). The most consistent findings with likely biological relevance were deletions of chromosomes 4 (consensus, 4q21-qter), 9 (consensus, 9p21-pter), 20p, and 3 (consensus, 3q12-q21). These regions have not been previously implicated in Wilms' tumor and may harbor novel genes that could aid attempts to understand the familial predisposition as well as the development and progression of these tumors.