Although most ovarian cancers (90%) occur spontaneously (i.e. by chance), 10% of women with ovarian cancer have inherited DNA alterations that predisposed them to ovarian cancer. Three hereditary syndromes can 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

A breast/ovarian cancer susceptibility gene is carried in ~10% of women with ovarian cancer. The risk to these women decreases with age and is estimated to be 14% for women 31-40 yrs of age, dropping to 7% for women 51-60 yrs of age. Gene carriers have a     > 15-fold increased risk of ovarian cancer relative to non-carriers. The lifetime risk for ovarian cancer in the general population is 1.3%, while estimates for gene carriers range from 10-60%. Mutations in BRCA1 and BRCA2 genes together have been estimated to account for 85% of breast-ovarian cancer families.
Both BRCA1 and BRCA2 genes are transmitted in an autosomal dominant fashion. Certain ethnic groups, such as Ashkenazi Jews, have high rates of specific mutations of these genes.

BRCA1. Mutations in BRCA1 are associated with increased risk for breast and ovarian cancer. The increased lifetime risk of breast cancer is estimated to be 55-85%, while the increased lifetime risk of ovarian cancer is 20-40%, with some studies setting it 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 under 30 years of age, and steadily declines with increasing age, dropping to 1.8% for women who are 61-70 years of age.  Consideration that suggest the involvement of BRCA1 mutation in the family include:

• Two or more cases of ovarian cancer in the family
• 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.  Mutations in the BRCA2 tumor suppressor gene are 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%. Mutations in BRCA2 are also associated with a 5-6% risk of male breast cancer, as well as increased risk of pancreatic cancer and melanoma. Indications of mutation in BRCA2 are similar to those outlined for BRCA1, and include a family history of pancreatic cancer in addition to breast and/or ovarian cancer.

2. Hereditary Non-Polyposis Colorectal Cancer (Lynch syndrome II)

Hereditary Non-Polyposis Colorectal Cancer (HNPCC), also known as Lynch syndrome II, is a hereditary syndrome associated with a significant lifetime risk of colorectal cancer (80%), and is typically diagnosed at age 40-50 yrs. Endometrial (uterine) cancer associated with HNPCC is ~40%, and the risk of ovarian cancer is ~10%. Stomach, small bowel, urinary tract, and biliary tract malignancies are also associated with HNPCC.

HNPCC is associated with germline mutations of mismatch repair [MMR] genes, causing widespread genomic instability, or a hypermutable state, which allows mutations to accumulate. Genetic testing is available for HNPCC, and involves five causative genes. Consideration that suggest the involvement of of HNPCC include:

• 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.

3. Site-specific Ovarian Cancer

Site-specific ovarian cancer syndrome refers to families that only demonstrate ovarian malignancy. This syndrome is the least common of the three hereditary cancer syndromes and is characterized by increased risk of ovarian cancer. It has been suggested that most families with this syndrome are linked to mutations in the BRCA1 gene.

Characteristic of Familial Ovarian Cancers. Familial ovarian cancers occur at a younger age than sporadic ovarian cancers. For BRCA-associated ovarian cancer, the average age at diagnosis is ~50 years, and ~40 years for HNPCC. 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 better than for sporadic cases. Overexpression of the HER2/neu gene in familial ovarian cancers often occurs.