Genetic Predisposition

To contain the costs to the population, chemoprevention or prophylactic surgery for ovarian cancer may be directed at high-risk groups. In the United States, a woman on average has a 1.4% lifetime risk of developing ovarian cancer. In contrast, the risk increases to 4% to 5% with one first-degree relative with ovarian cancer. With two first-degree relatives, the lifetime risk further increases to 7%. Approximately 10% of ovarian malignancies appear to be hereditary. Genetic predisposition should be suspected in a woman with a diagnosis of premenopausal breast cancer, with ovarian cancer in a family member at any age, and with cancers in multiple family members of two to four generations. Two hereditary syndromes are described.

Hereditary breast and ovarian cancer syndrome appears to be responsible for a preponderance of genetically linked malignancies of the ovary. BRCA1 and BRCA2 gene mutations are associated with this syndrome. Three high-frequency founder mutations have been described in Ashkenazi Jewish populations. Two founder mutations (185delAG and 5382insC) have been described for BRCA1 and one such mutation (6174delT) for BRCA2. Other less common mutations have been described. Deleterious BRCA1 and BRCA2 mutations confer a lifetime risk of ovarian cancer of 30% to 40% and 15% to 25%, respectively. BRCA mutation carriers also have an increased risk of fallopian tube cancer (lifetime risk 0.6%) and primary peritoneal cancer (lifetime risk 1.3%).3

Hereditary nonpolyposis colorectal cancer syndrome (HNPCC) is associated with the remaining known genetically linked ovarian cancer syndromes. It is caused by mutations in DNA mismatch repair genes and is linked to an increased risk of colon, endometrial, ovarian, urogenital, and other gastrointestinal malignancies. This syndrome is associated with a 5% to 10% lifetime risk of ovarian cancer (Table 4-1).

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