MOLECULAR MECHANISMS POSSIBLY AFFECTING WT1 FUNCTION IN HUMAN OVARIAN-TUMORS

The frequent allelic deletions observed on the short arm of chromosome 11 in ovarian tumors suggest that the WT1 gene, a proposed tumor-suppressor gene located on chromosome 11p13 and expressed in the human fetal genitourinary system, may contribute to the development of ovarian neoplasms. Structural and sequence analysis of the entire coding portions of the WT1 gene did not reveal any abnormalities in the 20 ovarian tumor specimens (13 of which showed 11p13 allelic deletions) and 5 cell lines which we analyzed. These findings invalidate the hypothesis that the WT1 gene functions as a classical tumor-suppressor gene in ovarian tumorigenesis and suggest that a different recessive oncogene may be ''exposed'' by the observed 11p13 allelic deletions. Expression analysis showed that the WT1 gene was transcriptionally active in all the tumors tested, but considerable variations in the mRNA levels were found. This apparent variability, which should be confirmed at the cellular level in the tumor specimens, was also observed in the ovarian tumor-cell lines. Finally, WT1 expression data were evaluated in conjunction with immunohistochemical data on p53. The possible functional effects of altered WT1 mRNA expression in ovarian tumors are discussed, taking into account the potential WT1/p53 protein interaction. (C) 1994 Wiley-Liss, Inc.