While approximately 90% of ovarian cancers occur sporadically (by chance), 10% of women with ovarian cancer have inherited genetic changes that predisposed them to ovarian cancer. There are three hereditary syndromes that predispose to ovarian cancer: 1. hereditary breast-ovarian cancer syndrome due to mutations in the tumor suppressor genes BRCA1 and BRCA2; 2. Hereditary Non-Polyposis Colorectal Cancer (Lynch syndrome); and 3. hereditary site-specific ovarian cancer.
1. Hereditary Breast-Ovarian Cancer Syndrome
Approximately 10% of women with ovarian cancer are carriers of a breast/ovarian cancer susceptibility gene. The proportion of cases of ovarian cancer due to such a gene decreases with age and is estimated to be 14% for women diagnosed in the fourth decade, dropping to 7% for women diagnosed in the sixth decade. Gene carriers have a greater than fifteen-fold risk of ovarian cancer compared to noncarriers. The lifetime risk for ovarian cancer in the general population is 1.3%, while estimates for gene carriers range from 10% to 60%. BRCA1 and BRCA2 together have been estimated to account for 85% of breast-ovarian cancer families.
Both BRCA1 and BRCA2 are transmitted in an autosomal dominant fashion. Certain ethnic groups, such as Ashkenazi Jews, have high rates of specific mutations of these genes. The large number of mutations described makes genetic testing and patient counseling complex, and illustrates the need for genetic counseling by a qualified health care provider.
BRCA1. BRCA1 is a gene associated with increased risk for breast and ovarian cancer. The lifetime risk of breast cancer is estimated to be 55-85%, while the lifetime risk of ovarian cancer is 20-40%, with some studies suggesting as high at 60%. The proportion of ovarian cancers in the general population attributable to this gene is estimated to be 5.9% for women in the third decade or younger, and steadily declines with increasing age, dropping to 1.8% in the seventh decade [Ford 95]. Features suggestive of a BRCA1 mutation include a family history of:
- Two or more cases of ovarian cancer
- Breast and ovarian cancer in the same woman
- One or more cases of pre-menopausal breast cancer with or without a case of ovarian cancer diagnosed at any age
- Two or more cases of post-menopausal breast cancer and one or more cases of ovarian cancer diagnosed at any age
- Male breast cancer
BRCA2.The BRCA2 tumor suppressor gene is also associated with high rates of breast and ovarian cancer. The lifetime risk of breast cancer has been reported to be similar to that of BRCA1 (55-85%), while the lifetime risk of ovarian cancer is estimated to be 10-20%. BRCA2 is also associated with a 5-6% risk of male breast cancer, as well as increased risk of pancreatic cancer and melanoma. BRCA2 features are similar to those outlined for BRCA1, but also include a family history of pancreas cancer in addition to breast and/or ovarian cancer. (For more information, see this article.)
2. Hereditary Non-Polyposis Colorectal Cancer (Lynch syndrome II)
3. Site-specific ovarian cancer
Hereditary Non-Polyposis Colorectal Cancer (HNPCC), also known as Lynch syndrome II, is a hereditary syndrome most commonly characterized by an increased risk for colorectal cancer. The lifetime risk of colorectal cancer is 80%, and is typically diagnosed in the individual's mid-40s. The risk of endometrial (uterine) cancer associated with HNPCC is approximately 40%, while the risk of ovarian cancer is 10%. Other associated cancers include stomach, small bowel, urinary tract, and biliary tract.
Germline mutations of mismatch repair [MMR] genes have been demonstrated in individuals with HNPCC causing widespread genomic instability, or a hypermutable state, which provides the background for an accelerated accumulation of mutations [Marra 95]. Genetic testing is available for HNPCC, but is complex because five causative genes have been identified, thus far. Again, genetic counseling is advised. Features strongly suggestive of HNPCC include:
Although not as strongly suggestive, HNPCC should be considered in a family with one case of early-onset colorectal cancer AND one case of ovarian cancer diagnosed at any age.
- Three or more closely related family members with colorectal cancer or another HNPCC-associated cancer, AND
- Colorectal cancer involving at least two generations, AND
- One or more colorectal cancer cases diagnosed before age 50 years.
Limited data are available on the site-specific ovarian cancer syndrome. This is the least common of the three hereditary cancer syndromes, and is characterized by an increased risk of ovarian cancer. Findings from one group of investigators suggested that most families with this syndrome are linked to mutations in the BRCA1 gene.
Features of familial ovarian cancers. Ovarian cancer in women with familial ovarian cancer occurs at a younger age than sporadic ovarian cancer. For BRCA-associated ovarian cancer, the average age at diagnosis is about 50 years, and for HNPCC, 40 years. The stage distribution is similar to sporadic cases. Tumors are usually papillary serous carcinomas with similar features to sporadic tumors. The prognosis for BRCA-associated familial cases appears to be somewhat better than for sporadic cases. Molecular studies of familial ovarian cancers suggest a higher than expected proportion of ovarian tumors showing overexpression of HER2/neu.