Identification and characterization of candidate tumor suppressor genes potentially involved in the etiology of ovarian cancer

Over the last century it has become widely accepted that cancer is a genetic disease. Initiation and progression of cancer results from the accumulation of mutations in at least three classes of cellular genes. In this aspect the genetics of ovarian cancer have remained poorly understood with respect to other diseases. During tumorigenesis, many of the documented changes in cellular DNA involve inactivation of tumor suppressor genes. In this aspect, molecular analyses of ovarian cancer specimens indicate that several tumor suppressor genes may be involved in the etiology of this disease. Loss of heterozygosity for polymorphic markers on a chromosome arm is often indicative of the inactivation of a tumor suppressor on that chromosome based on Knudson's "two-hit" hypothesis. Allelic loss studies in a large series of ovarian tumors identified several candidate tumor suppressor loci on chromosome 9. Mutational analysis of CDKN2A/p16 on 9p21 in ovarian tumors revealed a minor role for the inactivation of this gene in ovarian cancer. Overall, these studies suggest the potential involvement of a gene or genes on chromosome 9q in the progression of this disease.; Molecular analyses of ovarian cancers indicate that allelic loss on chromosome 17 is the most frequently observed alteration in this tumor type. Based on allelic loss studies in brain, breast, and ovarian tumours, a second tumor suppressor gene distinct from TP53 is hypothesized to exist on chromosome 17p. Positional cloning strategies identified two novel candidate tumor suppressor genes, referred to as OVCA1 and OVCA2, that map to 17p13.3. Analysis of the amino acid sequence suggests that OVCA1 is a member of a previously unidentified gene family. In this aspect a transcript encoding a related protein but unique from OVCA1 was cloned that maps to 1p34. Evolutionary conservation of amino acid residues within these two proteins has described new functional motifs with previously uncharacterized biochemical activity. Mutational analysis of OVCA1 identified several sequence variants. Western blot analysis of tumor extracts revealed that OVCA1 is significantly reduced in approximately 30% and 60% of ovarian and breast tumors analyzed, respectively. Reintroduction of OVCA1 into the ovarian cancer cell line A2780 produced a 50% to 60% reduction of clonal outgrowth. Maintenance of exogenous OVCA1 expression in clonal populations of cells resulted in a reduced growth rate that correlated with increased populations of cells in the G{dollar}sb1{dollar} fraction of the cell cycle when compared to controls and the parental cell line. The location, reduced expression in ovarian tumors, and ability of OVCA1 to suppress cell growth suggest that decreased expression of OVCA1 may contribute to ovarian tumorigenesis.