Does hereditary predisposition account for the majority of epithelial ovarian cancers?

From the Guidelines

No, hereditary predisposition does not account for the majority of epithelial ovarian cancers. According to the American Society of Clinical Oncology (ASCO) guideline on germline and somatic tumor testing in epithelial ovarian cancer 1, approximately 25% of all ovarian cancers are caused by a heritable genetic condition. The most common genetic mutations associated with ovarian cancer are BRCA1 and BRCA2, which account for almost 40% of ovarian cancers in women with a family history of the disease. However, this still leaves a significant proportion of ovarian cancers that are not attributed to hereditary predisposition.

Some key points to consider include:

• The strongest risk factor for ovarian cancer is a family history of breast or ovarian cancer 1
• Mutations in BRCA1 and BRCA2 account for almost 40% of ovarian cancers in women with a family history of the disease 1
• Approximately one quarter (6% of all ovarian/fallopian tube/peritoneal cancers) are caused by genes other than BRCA1 and BRCA2, including many genes associated with the Fanconi anemia pathway or otherwise involved with homologous recombination 1
• The remaining 75-80% of epithelial ovarian cancers are considered sporadic, developing due to acquired genetic changes throughout a woman's lifetime rather than inherited mutations.

Understanding the distinction between hereditary and sporadic ovarian cancer is crucial for appropriate genetic counseling, risk assessment, and preventive strategies for patients and their families. As such, genetic testing is recommended for all women diagnosed with ovarian cancer, regardless of family history, to identify potential hereditary genetic mutations and inform personalized management strategies 1.

From the Research

Hereditary Predisposition in Epithelial Ovarian Cancers

• Hereditary factors play a significant role in the development of epithelial ovarian cancers, with studies suggesting that at least 10% of all epithelial ovarian cancers are hereditary 2, 3, 4.
• The majority of hereditary ovarian cancers are associated with germ line mutations in the BRCA1 and BRCA2 tumor suppressor genes, accounting for approximately 90% of cases 2.
• Other genes, such as those involved in the DNA mismatch repair (MMR) pathway, also contribute to hereditary ovarian cancer, although to a lesser extent 2, 5, 6.
• The cumulative lifetime risk of ovarian cancer is estimated to be 40% to 50% for BRCA1 mutation carriers and 20% to 30% for BRCA2 mutation carriers 2, 3.
• Hereditary ovarian cancers often exhibit distinct clinicopathologic features compared to sporadic cancers, including a younger age at diagnosis and a higher grade of cancer 2, 3.

Genetic Landscape and Risk Assessment

• Next-generation sequencing (NGS) has enabled the simultaneous testing of multiple genes, increasing the complexity of genetic testing but also allowing for more accurate risk assessment 5, 6.
• Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) that contribute to the familial risk of ovarian cancer, although an unknown proportion of the genetic component of EOC risk remains unexplained 6.
• The use of polygenic risk scores may help predict individual cancer risk more accurately, taking into account the combined effects of multiple genetic variants 6.

Clinical Implications and Risk Reduction Strategies

• Women with a family history of breast and/or ovarian cancer should undergo genetic testing and consider risk-reducing strategies, such as prophylactic oophorectomy or salpingo-oophorectomy 2, 3.
• Annual follow-up is recommended for women with a family history of ovarian cancer, particularly those with mutations in the BRCA1 or BRCA2 genes 2.
• The identification of women with homologous recombination (HR)-deficient EOCs has significant clinical implications, concerning chemotherapy regimen planning and the use of targeted therapies such as poly(ADP-ribose) polymerase (PARP) inhibitors 5.