Epidemiological and Genetic Factors Associated With Ovarian Cancer

Genetic Risk Factors for Ovarian Cancer

As mentioned previously, the 2 most common hereditary cancer syndromes associated with ovarian cancer include HOBC/HOC and HNPCC (Lynch syndrome).^[22,23] These patients are considered to be at high risk for ovarian cancer, and the distinction between the hereditary types is based on which genetic mutation is involved in tumor development.

Hereditary Breast and Ovarian Cancer

Women who carry disease-specific alleles for BRCA1 and BRCA2 are at significantly higher risk for epithelial ovarian cancer than women in the general population.^[1,2,22,23] The BRCA1 gene is an oncosuppressor gene located on chromosome 17q that was identified in 1994.^[13] It contains small deletions or insertions that result in premature stop codons that shorten (truncate) its protein product.^[13] Alterations in this gene are found in 75% of families with HBOC. The BRCA1 gene participates in chromatin remodeling processes, interacts with the retinoblastoma (Rb) gene, and is a key member of the histone deacetylase complex. This gene participates in crucial steps within the cell cycle. When mutations occur, cellular growth controls are unchecked, which results in tumorigenesis.

The BRCA2 gene, located on chromosome 13q, is found in 10% to 20% of HBOC and was isolated a year after the BRCA1 gene.^{[11,13,22,23]} The BRCA1 and BRCA2 genes share sequence homology, although, relatively speaking, the BRCA2 gene is associated with a higher risk for breast than ovarian cancer compared with BRCA1. BRCA2 is also associated with male breast cancer, as well as prostate and pancreatic cancer.

Although no standard clinical definition of HBOC exists, several general characteristics are used to identify affected families. These familial characteristics include (1) several cases of breast cancer diagnosed before the age of 50 years, (2) one or more relatives with ovarian cancer, (3) one or more relatives with both breast and ovarian cancer, and (4) the presence of a BRCA1 or BRCA2 germ-line mutation. Ovarian cancers associated with BRCA1/2 are typically high-grade serous carcinomas, but with a relatively favorable clinical course.

HNPCC/Lynch Syndrome

Hereditary nonpolyposis colorectal cancer/Lynch syndrome is an autosomal, dominant syndrome, where the mean age of onset of colorectal cancer is 45 years old.^[13] Families that exhibit HNPCC/Lynch syndrome including colorectal cancer have an increased risk for endometrial, ovarian, gastric, pancreatic, and biliary tract cancers.^[13,22,23] Unlike HBOC, HNPCC has a standardized clinical definition, termed the Amsterdam II criteria. These criteria include (1) 3 or more relatives with colorectal or other Lynch-associated cancer, one of whom is a first-degree relative to one of the other two; (2) affected members in at least 2 generations; (3) at least 1 Lynch-associated diagnosis in the family before age 50 years; and (4) exclusion of a diagnosis of familial adenomatous polyposis.

Hereditary nonpolyposis colorectal cancer/Lynch syndrome is a result of mutations in MMR genes that are found on at least 4 chromosomes (2p, 3p, 7p, 2q). These genes form heterodimers, which recognize and repair DNA mistakes during transcription. Mutations in MMR genes are associated with a 9% to 12% increase in the risk for ovarian cancer. Unlike the BRCA1/2-associated tumors, ovarian tumors that develop from this genetic mutation represent all histopathologic types.^[13,22] Autosomal dominant mutations such as HNPCC have a 50% chance of being transferred to offspring of the affected parent.^[13] In addition, these mutations are highly penetrant, meaning there is a high probability of developing one of the tumors associated with HNPCC at some point during the offspring's lifetime.

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