Most epithelial ovarian cancer is sporadic, with familial or hereditary patterns accounting for 5% 10% of all malignancies. The risk of ovarian cancer is higher than that of the general population in women with certain family histories. Most familial ovarian cancer is associated with mutations in BRCA1, BRCA2 or DNA mismatch repair genes in the human nonpolyposis colon cancer (HNPCC, Lynch Type II) syndrome. There have also been reportable cases of ovarian cancer associated with Li-Fraumini syndrome that occurs due to p53 mutations in the germ line. In the past, it had been thought that there were two distinct syndromes associated with a genetic risk, site-specific hereditary ovarian cancer, and hereditary breast/ovarian cancer syndrome. However, it is now believed that these groups essentially represent a continuum of mutations with different degrees of penetrance within a given family.

BRCA1 and BRCA2
The majority of ovarian cancer families have mutations in the BRCA1 gene that is located on chromosome 17. A small fraction of inherited disease has been traced to another gene, BRCA2, located on chromosome 13. Discovered through linkage analyses, these two genes are associated with the genetic predisposition to both ovarian and breast cancer.

BRCA1/2 mutations are passed via autosomal dominant inheritance, and a full pedigree analysis (ie, both maternal and paternal sides of the family) must be carefully evaluated. There are numerous distinct mutations that have been identified on each of these genes, and the mutations have different degrees of penetrance which 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 has been calculated to be as high as 27% for those women with a BRCA2 mutation. The risk of breast cancer in women with a BRCA1 or BRCA2 mutation may be as high as 56% to 87%.

Hereditary ovarian cancers generally occur in women about 10 years younger than those with nonhereditary tumors. As the median age of epithelial ovarian cancer is in the mid- to late 50s, a woman with a first- or second-degree relative who had premenopausal ovarian cancer may have a higher probability of carrying an affected gene.

Within a given family, a combination of epithelial ovarian and breast cancers can affect a mixture of first- and second-degree relatives. Women with this syndrome tend to develop cancers at a young age, and breast cancers may be bilateral. If two first-degree relatives are affected, this pedigree is consistent with an autosomal dominant mode of inheritance.

Founder Effect
More than 100 different mutations of BRCA1 and BRCA2 have been cataloged in different families with ovarian and breast cancer. A particularly high carrier rate of BRCA1 and BRCA2 mutations has been found in women of Ashkenazi Jewish descent and in Islandic women. Three specific mutations occur repeatedly in the Ashkenazi population and are associated with many of the breast and ovarian cancer families: 185delAG and 5382insC in BRCA1, and 6174delT in BRCA2. One in 40 or 2.5% of all Ashkenazi Jewish women carry at least one of these three mutations. The prevalence of these specific mutations in the Ashkenazi population is thought to have resulted from a “founder effect”, where the mutations can be traced to particular families within a defined geographic area.

Pedigree Analysis
The risk of ovarian cancer depends on the number of first- and/or second-degree relatives with a history of epithelial ovarian carcinoma and/or breast cancer, and on the number of malignancies that occur at an early age. The degree of risk is difficult to determine precisely unless one performs a full pedigree analysis.

In families with two first-degree relatives (ie, mother, sister, or daughter) with documented premenopausal epithelial ovarian cancer, the risk that a female first-degree relative will have an affected gene could be as high as 35% - 40%. In families with a single first-degree relative and a single second-degree relative (ie, grandmother, aunt, first cousin, or granddaughter) with epithelial ovarian cancer, the risk that a woman will have an affected gene also may be increased. The risk may be two- to tenfold higher than in those without a familial history of the disease. In families with a single post-menopausal first-degree relative with epithelial ovarian carcinoma, a woman may not have an increased risk of having an affected gene because the case is most likely to be sporadic. However, if the ovarian cancer occurred in a premenopausal relative, this could be significant, and a full pedigree analysis should be undertaken. Women with a primary history of breast cancer have twice the expected incidence of subsequent ovarian cancer.

Lynch Type II Syndrome
The hereditary nonpolyposis colorectal cancer (HNPCC) syndrome includes multiple adenocarcinomas, including familial colon, ovarian, endometrial, and breast cancers, as well as other malignancies of the gastrointestinal and genitourinary systems. Mutations of DNA mismatch repair genes have been associated with this syndrome including mutations of MSH2, MLH1, PMS1 and PMS2. The risk that a woman who is a member of a Lynch type II family will develop epithelial ovarian cancer depends on the frequency of this disease in her first- and second-degree relatives, although these women appear to have at least three times the relative risk of the general population.

Management of Women at High-Risk for Ovarian Cancer
The management of a woman with a strong family history of epithelial ovarian cancer must be individualized and depends on her age, her reproductive plans, and the extent of risk. In all of these syndromes, women at risk benefit from a thorough pedigree analysis. A geneticist should evaluate the family pedigree for at least three generations. Decisions about management are best made after careful study and, whenever possible, verification of the histologic diagnosis of the family members’ ovarian cancer.

The value of testing for BRCA1 and BRCA2 has yet to be clearly established, although some guidelines for testing now exist. The importance of genetic counseling cannot be overemphasized, as decisions surrounding genetic testing are complex. The American Society of Clinical Oncologists has offered guidelines that emphasize careful evaluation by geneticists, careful maintenance of medical records, as well as a clear understanding in a genetic screening clinic of how to counsel and manage these patients. Concerns remain regarding how the information will be used, the impact on insurability, how the results will be interpreted and how the information will be applied within a specific family (eg, to counsel children). Although there are conflicting data, the behavior of breast cancers arising in women with germ-line mutations in BRCA1 or BRCA2 is comparable to that of sporadic breast cancers. Women with breast cancer who carry these mutations are, however, at a greatly increased risk of ovarian cancer as well as a second breast cancer.

Although recommended by the NIH Consensus Conference on Ovarian Cancer, the value of screening with transvaginal ultrasonography, CA 125 levels, or other procedures has not been clearly established in women at high risk. Bourne and colleagues have shown that this approach can detect tumors about ten times more often than in the general population, and thus they recommend screening in high-risk women.

Data derived from a multi-institutional consortium of genetic screening centers indicate that the use of the oral contraceptive pill is associated with a lower risk of developing ovarian cancer in women who have a mutation in either BRCA1 or BRCA2. The risk reduction is significant: in women who have taken the oral contraceptive pill for 5 or more years, the relative risk of ovarian cancer is 0.4, or a 60% reduction in the incidence of the disease.

The value of prophylactic oophorectomy in women with BRCA1/2 mutations has been clearly documented. The risk of ovarian cancer is substantially diminished, but there remains the low risk of primary peritoneal carcinoma, a tumor that may also have a higher incidence in women who have mutations in the BRCA1 and BRCA2. Women at high risk for ovarian cancer who undergo prophylactic oophorectomy can harbor occult neoplasia. In one series of 42 such operations, 4 (9.5%) of patients had a malignancy, one was detected at surgery and 3 were found only on microscopic examination. Performance of a prophylactic oophorectomy also appears to lower the risk of breast cancer by about 54%. Women who carry these germ-line mutations are at higher risk for fallopian tube cancer; a complete bilateral salpingo-oophorectomy should be performed when they undergo prophylactic surgery.

Current recommendations for management of women with high-risk for ovarian cancer have been summarized. Women who appear to be at high-risk for ovarian and or breast cancer should undergo genetic counseling and, if the risk appears to be substantial, may be offered genetic testing for BRCA1 and BRCA2. Women who wish to preserve their reproductive capacity can undergo periodic screening by transvaginal ultrasonography every 6 months, although the efficacy of this approach is not clearly established. Prophylactic surgery (bilateral salpingo-oophorectomy with or without a hysterectomy) is the treatment of choice for women who have completed their childbearing. Oral contraceptives should be recommended to young women before a planned family. Women who do not wish to maintain their fertility or who have completed their family may undergo prophylactic bilateral salpingo-oophorectomy. The risk should be clearly documented, preferably established by BRCA1 and BRCA2 testing, before salpingo-oophorectomy. These women should be counseled that this operation does not offer absolute protection, as peritoneal carcinomas occasionally can occur after bilateral oophorectomy. In women who also have a strong family history of breast cancer, annual mammographic screening should be performed commencing at age 30 years. Women with a documented HNPCC syndrome should be treated as above, and in addition, should undergo periodic screening mammography, colonoscopy, and endometrial biopsy.

In a recent study, Markov modeling was performed in a simulated cohort of 30-year-old women who tested positive for BRCA1/2 mutations. Quality adjustment of survival estimates were obtained from a survey of women aged 33 to 50 years. A 30-year-old woman could prolong her survival beyond that associated with surveillance alone by 1.8 years with tamoxifen, 2.6 years with prophylactic oophorectomy, 4.6 years with both tamoxifen and prophylactic oophorectomy, 3.5 years with prophylactic mastectomy and 4.9 years with both surgeries. Quality adjusted survival could be prolonged by 2.8 years with tamoxifen, 4.4 years with prophylactic oophorectomy, 6.3 years with tamoxifen and oophorectomy and 2.6 years with mastectomy or both operations. Benefits would decrease if institution of these preventive measures were delayed beyond age 30.