What are the genetic risk factors for ovarian cancer?

Updated: Aug 10, 2020
  • Author: Andrew E Green, MD; Chief Editor: Yukio Sonoda, MD  more...
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Family history plays an important role in the risk of developing ovarian cancer. The lifetime risk for developing ovarian cancer is 1.6% in the general population. This compares with a 4-5% risk when 1 first-degree family member is affected, rising to 7% when 2 relatives are affected. From 5-10% of cases of ovarian cancer occur in an individual with a family history of the disease. Only a small percentage of these patients have an inherited genetic abnormality, and the risk of this occurrence increases with the strength of the family history. Hereditary epithelial ovarian cancer occurs at a younger age (approximately 10 years younger) than nonhereditary epithelial ovarian cancer, but the prognosis may be somewhat better.

Integrated genomic analyses by the Cancer Genome Atlas Research Network have revealed high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumors. The findings also include the low prevalence but statistically recurrent somatic mutations in 9 further genes, including NF1, BRCA1, BRCA2, RB1, and CDK12, along with 113 significant focal DNA copy number aberrations and promoter methylation events involving 168 genes. Pathway analyses revealed defective homologous recombination in about half of all tumors, and that NOTCH and FOXM1 signaling are involved in serous ovarian cancer pathophysiology. [15]

Evidence from the Cancer Genome Atlas Network showed that serous ovarian tumors and breast basal-like tumors shared a number of molecular characteristics, such as the types and frequencies of genomic mutations, suggesting that ovarian and breast cancer may have a related etiology and potentially similar responsiveness to some of the same therapies. [16]

At least two syndromes of hereditary ovarian cancer are clearly identified, involving either (1) disorders of the genes associated with breast cancer, BRCA1 and BRCA2, or (2) more rarely, genes within the Lynch II syndrome complex. Breast/ovarian cancer syndrome is associated with early onset of breast or ovarian cancer. Inheritance follows an autosomal dominant transmission. It can be inherited from either parent.

Most cases are related to the BRCA1 gene mutation. BRCA1 is a tumor suppressor gene that inhibits cell growth when functioning properly; the inheritance of mutant alleles of BRCA1 leads to a considerable increase in risk for developing ovarian cancer.

Approximately 1 person in 4000 in the general population carries a mutation of BRCA1. Some populations have a much higher rate of BRCA1 and BRCA2 mutations, especially Ashkenazi Jews. In families with 2 first-degree relatives (mother, sister, or daughter) with premenopausal epithelial ovarian cancer, the likelihood of a female relative having an affected BRCA1 or BRCA2 gene is as high as 40%. The probability is much lower when the disease occurs in relatives postmenopausally.

Individuals with a BRCA1 gene mutation have a 50-85% lifetime risk of developing breast cancer and a 15-45% risk of developing epithelial ovarian cancer. Those with a BRCA2 gene mutation have a 50-85% lifetime risk of developing breast cancer and a 10-20% risk of developing epithelial ovarian cancer. Families with BRCA2 mutations are at risk for developing cancer of the prostate, larynx, pancreas, and male breast.

Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers; however, in an investigation of a common genetic variation at the 9p22.2 locus, a decreased risk of ovarian cancer was noted in carriers of a BRCA1 or BRCA2 mutation. [17]

Families with Lynch II syndrome or hereditary nonpolyposis colorectal cancer are characterized by a high risk for developing colorectal, endometrial, stomach, small bowel, breast, pancreas, and ovarian cancers. This syndrome is caused by mutations in the mismatch repair genes. Mutations have been demonstrated in mismatch repair genes MSH2, MLH1, PMS1, and PMS2.

Women with a history of breast cancer have an increased risk of epithelial ovarian cancer.

In a study by Rafner et al, whole-genome sequencing identified a rare mutation in BRIP1, which behaves like a classical tumor suppressor gene in ovarian cancer. [18] This allele was also associated with breast cancer.

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