EPITHELIAL OVARIAN CARCINOMAS
with family histories of ovarian cancer. Two genes involved in this syndrome have been cloned (BRCA1 and The epithelial ovarian carcinomas represent approxi-BRCA2), and mutations in these genes appear to be mately 90% of human ovarian malignant neoplasms. responsible for a high proportion of cancers in women In Europe and North America, these carcinomas are with familial cancer histories. The importance of the the fourth most common cause of death from cancer BRCA2 gene in ovarian cancer has not been clearly among women and the prime cause of death from gynedefined. In contrast, BRCA1 plays a major role in ovarcological malignancies. The overall 5-year survival is ian cancer susceptibility (5). Germline mutations in only 30 -40% because most cases are detected in late BRCA1 account for about 45% of families with instages and respond poorly to therapy. Screening tests creased breast cancer, for at least 80% of families with are available for patient follow-up and for the detection increases in both breast and ovarian cancer, and for of advanced cases. However, there are no reliable about 10% of sporadic (nonfamilial) ovarian cancers. A means for early detection except for genetic screening woman carrying a BRCA1 mutation has a 40% and in a small group of women with family histories of 80% chance, respectively, to develop ovarian and breast breast or ovarian cancer and, to date, no screening test cancer by age 70. Intensive screening for BRCA1 mutahas been shown to reduce mortality (1,2).
tions is going on, but the gene is large and to date more The risk in the general population of developing ovarthan 65 distinct BRCA1 mutations have been found, ian cancer is 1.4% (1:70). This risk increases with inferand this complexity makes screening and risk predictility and nulliparity and decreases with pregnancies tions difficult (6). BRCA1 is located at 17q21 and enand with oral contraception, suggesting that the numcodes a 1863 aa polypeptide. Reports on its function ber of ovulations may influence ovarian carcinogenesis. have been contradictory, but the protein structure sug-Perhaps the most important risk factor known at presgests that it is a nuclear transcription factor. In the ent is a family history of ovarian cancer, which influadult, mRNA for BRCA1 occurs mostly in testis, thyences about 5 -10% of cases. The risk increases from mus, ovary, and breast; in the embryo, it is found in 1.4% in the general population to 5% for women with rapidly proliferating cells undergoing differentiation one first-degree relative and to 8% for women with two (7). BRCA1 may be a tumor-suppressor gene because first-degree relatives affected. There is also a strong BRCA1 mutations are associated with early-onset canasociation with familial breast cancer and a lesser assocer and with bilaterality of breast cancer and because ciation with familial cancers of the colon and endomeintroduction of wtBRCA1 causes growth inhibition in trium (3). Three hereditary ovarian cancer syndromes breast and ovarian cancer lines (8). with autosomal dominance have been described.
In terms of histopathology, most epithelial ovarian carcinomas express complex phenotypic characteristics Hereditary site-specific ovarian cancer of Mullerian duct-derived epithelia, i.e., the oviduct, A family history of ovarian cancer only is associated endometrium, and uterine cervix (9,10). At the cellular with an overall 3.6-fold increase in risk. No specific level, these include apical microvilli and cilia, juncgene responsible for this syndrome has been indentified tional complexes, epithelial membrane antigens, and to date.
secretory products including mucins and CA125. At the level of multicellular morphogenesis, the tumors form Hereditary nonpolyposis colon and ovarian polarized epithelia, papillae, cysts, and glandular cancer (Lynch syndrome II, or HNPCC) structures. These complex, highly differentiated tu-Ovarian cancer occurs in families that also have a mors arise in a simple squamous-to-cuboidal epithehigh incidence of carcinomas of the colon and endomelium, the ovarian surface epithelium (OSE), which is trium. In this syndrome, the exact increase in risk has not been defined. It is associated with mutations in the DNA mismatch repair genes hMSH1, hMSH2, hPMS1, Contract grant sponsor: Medical Research Council of Canada; and hPMS2 (4).