Hereditary ovarian cancers occur in women approximately 10 years younger than those with nonhereditary tumors (i.e., closer to age 50 compared to age 60 for those with sporadic cancer) (59). A woman with a first-or second-degree relative who had premenopausal ovarian cancer may have a higher probability of carrying an affected gene. Breast and ovarian cancer may exist in a family in which there is a combination of epithelial ovarian and breast cancers, affecting a mixture of first-and second-degree relatives. Women with this syndrome tend to have these tumors at a young age, and the breast cancers may be bilateral. If two first-degree relatives are affected, this pedigree is consistent with an autosomal dominant mode of inheritance (50,58). Most BRCA1 ovarian cancers are high-grade serous carcinomas (Fig. 37.9).
There is a higher carrier rate of BRCA1 and BRCA2 mutations in women of Ashkenazi Jewish descent, in Icelandic women, and in many other ethnic groups (64,65,67–69). There are three specific founder mutations carried by the Ashkenazi population, 185delAG and 5382insC on BRCA1, and 6174delT on BRCA2. Individuals of Ashkenazi Jewish descent have a 1 in 40, or 2.5%, chance of having a mutation in BRCA1 or BRCA2, and thus there is a greater risk in this population. The increased risk is a result of the founder effect, in which a higher rate of specific mutations occurs in an ethnic group from a defined geographic area. These founder mutations generated considerable interest, because they facilitate studies of prevalence and penetrance and can be used to quantify the degree of homogeneity within a population.
CHAPTER 37 Ovarian, Fallopian Tube, and Peritoneal Cancer
Figure 37.9 BRCA1-associated ovarian carcinoma is typically a high-grade serous adenocarcinoma with numerous mitotic figures and marked nuclear pleomorphism. A brisk lymphocytic infiltrate with tumor infiltrating lymphocytes is not uncommon in these tumors.
The risk of carrying a germline mutation that predisposes to ovarian cancer depends on the number of first-or second-degree relatives (or both) with a history of epithelial ovarian carcinoma or breast cancer (or both) and on the number of malignancies that occurs at an earlier age. The degree of risk is difficult to determine precisely unless a full pedigree analysis is performed.
1.
In families with two first-degree relatives (i.e., mother, sister, or daughter) with documented premenopausal epithelial ovarian cancer, the risk that a female first-degree relative has an affected gene could be as high as 35% to 40% (60).
2.
In families with a single first-degree relative and a single second-degree relative (i.e., grandmother, aunt, first cousin, or granddaughter) with epithelial ovarian cancer, the risk that a woman has an affected gene may be increased. The risk may be two-to 10-fold higher than in those without a familial history of the disease (60).
3.
In families with a single postmenopausal 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. If the ovarian cancer occurs in a premenopausal relative, this could be significant, and a full pedigree analysis should be undertaken.
4.
Women with a primary history of breast cancer have twice the expected incidence of subsequent ovarian cancer (59).