OVCA1: emerging as a bona fide tumor suppressor.

Abstract

Listen

Translate article

Despite the fact that ovarian cancer is the leading cause of death from gynecological disease in American women leading to an estimated number of more than 14,000 deaths in 2003 (American Cancer Society 2003), the molecular events occurring during ovarian tumorigenesis have not been unraveled in great detail. The discovery of these molecular events has proven particularly difficult for ovarian cancer, in part because this type of cancer is often discovered at late stages, limiting the availability of material for studies of the initiating events in ovarian cancer (Cvetkovic 2003). The pursuit of genes critical for ovarian tumorigenesis has nonetheless revealed a number of genes that may be implicated. Loss of heterozygosity (LOH) studies have established that chromosome 17 is a hotspot for chromosomal aberrations in breast (Phelan et al. 1998) and ovarian cancer (Eccles et al. 1992; Foulkes et al. 1993; Phillips et al. 1993, 1996b; Godwin et al. 1994; Saretzki et al. 1997; Wiper et al. 1998). Candidate oncogenes and tumor suppressors located on this chromosome include P53, BRCA1, HER2/NEU, NF1, NM23, HIC1, and the two recently discovered putative tumor suppressor genesOVCA1 andOVCA2 (for review, see Schuijer and Berns 2003; Fig. 1). P53 is the most frequently mutated gene in advanced epithelial ovarian carcinomas. However, in benign and borderline ovarian neoplasms, P53 mutations are relatively rare; suggesting that p53 loss-of-function is a late event in ovarian carcinogenesis (Godwin et al. 1997). The two breast cancer genes, BRCA1 and BRCA2, are often mutated in women with a family history of ovarian and breast cancer. However, BRCA1 and BRCA2 do not appear to be linked to the development of sporadic ovarian cancer, which accounts for the large majority of ovarian cancer cases. Recently, a novel interesting putative oncogene, EMSY, was found to be amplified in a large proportion (17%) of late stage ovarian carcinomas (Hughes-Davies et al. 2003). Interestingly, EMSY amplification was only observed in breast and ovarian cancer. EMSY associates with BRCA2, and overexpression may imitate loss of BRCA2 in both sporadic breast and ovarian cancer. Because no cases of amplification were found in lowergrade ovarian tumors, EMSY amplification is likely to be a late event in ovarian tumorigenesis. This unfortunately limits its use as a diagnostic marker for early detection. However, EMSY activation in concert with deactivation of tumor suppressor genes may be an important tumorigenic event. Further studies are needed to firmly establish EMSY as a significant ovarian oncogene.