Given the false-positive and false-negative results for both CA125 and transvaginal ultrasonography and the absence of good data to show that screening detects ovarian cancers at an earlier stage, these tests are not recommended and should not be used routinely to screen women with a population risk or high risk for ovarian cancer (54–56). In the future, new markers or technologies may improve the specificity of ovarian cancer screening, but proof of this will require a large, prospective study (47,48). Screening in women who have a familial risk may have a better yield, but to date there is no evidence to demonstrate a benefit of screening even in high-risk women, and this is being actively investigated (55,57). The findings of two prospective studies of annual transvaginal ultrasound and CA125 screening in 888 BRCA1and BRCA2 mutation carriers in the Netherlands and 279 mutation carriers in the United Kingdom are not encouraging and suggest a very limited benefit of screening in high-risk women (55,56). Despite annual gynecologic screening Hermsen et al. reported that a high proportion of ovarian cancers in BRCA1-2 carriers were interval cancers and the large majority of all cancers diagnosed were at advanced stages; similar results were reported by Woodward et al. (55,56).
Genetic Risk for The lifetime risk of ovarian carcinoma for women in the United States is about 1.4% (1–3). The Epithelial Ovarian risk of ovarian cancer is higher than that in the general population in women with certain family Cancer histories (51–60). Most epithelial ovarian cancer is sporadic, with familial or hereditary causes accounting for 5% to 10% of invasive epithelial ovarian cancer (59).
Most hereditary ovarian cancer is associated with mutations in the BRCA1 gene, located on chromosome 17 (58–69). A small proportion of inherited disease is associated with germline mutations in another gene, BRCA2, located on chromosome 13 (60). Discovered through linkage analyses, these two high-penetrance genes are associated with the genetic predisposition to both ovarian and breast cancers. There are almost certainly other low-to moderate-penetrance genes that predispose to ovarian and breast cancer, and this is an area of intense research interest (1).
It was thought that there were two distinct syndromes associated with a genetic risk, site-specific hereditary ovarian cancer and hereditary breast-ovarian cancer syndrome. It is now believed that these groups represent a continuum of mutations with different degrees of penetrance within a given family (62,70). There is a higher-than-expected risk of ovarian and endometrial cancer in Lynch syndrome, known as the hereditary nonpolyposis colorectal cancer syndrome (HNPCC syndrome) (71).
The mutations are inherited in an autosomal dominant fashion, and therefore a full pedigree analysis (i.e., both maternal and paternal sides of the family) must be carefully evaluated (62). There are numerous distinct mutations that were identified on each of these genes, and the mutations have different degrees of penetrance that may account for the preponderance of either breast cancer, ovarian cancer, or both, in any given family. Based on analysis of women who have a mutation in the BRCA1 gene and are from high-risk families, the lifetime risk of ovarian cancer may be as high as 28% to 44%, and the risk was calculated to be as high as 27% for those women with a BRCA2 mutation (59,60,66–69). The risk of breast cancer in women with a BRCA1 or BRCA2 mutation may be as high as 56% to 87%.