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Key Points

  • Disease summary:

    • Breast cancer is a common disease panethnically. Approximately 15% to 20% of breast cancer is thought to cluster in families while only 5% to 10% is caused by single gene defects.

    • Ovarian cancer is far less common; approximately 10% to 25% of ovarian cancer is caused by single gene defects.

    • The monogenic form of breast and ovarian cancer, hereditary breast and ovarian cancer (HBOC), caused by mutation in BRCA1 and BRCA2 predisposes individuals and families to a high lifetime risk of breast and ovarian cancers as well as other cancers including the prostate and pancreas. BRCA1-specific lifetime risk for female breast cancer is 55% to 65%, with a 39% risk for ovarian cancer. BRCA2-specific lifetime risk for female breast cancer is 47%, with a 11% to 17% risk for ovarian cancer. BRCA-related male breast cancer risk is 7% with a 20% risk for prostate cancer.

    • CHEK2-related breast cancer is a more recently described disease association. Mutations in CHEK2 within the context of a strong family history of breast cancer pose an increased risk, though there is much controversy around actual risk assessments. Studies within a European population, where a single mutation is common (1100delC), report a baseline risk of 6%, with that risk increasing to 44% in families in which two other relatives have a breast cancer diagnosis.

    • Genome-wide association studies (GWAS) have identified 11 loci that have repeatedly been associated with breast cancer in at least two published studies, see Table 52-1. Interestingly a study by Bolton et al. found a risk association for ovarian cancer which overlaps the observed risk for breast cancer at 19q13.11. This may indicate a BRCA1- and/or BRCA2-associated pathway driving these risks. The other observed associations may ultimately reveal new cancer risk pathways or new insights into the one associated pathway.

Table 52-1Eleven Loci Repeatedly Associated With Breast Cancer Risk in GWAS

  • Hereditary basis:

    • HBOC is an autosomal dominant cancer predisposition syndrome; some individuals with a disease-causing mutation may not develop an associated cancer in their lifetime, giving the appearance that the disease may skip generations.

    • CHEK2 also exhibits an autosomal dominant pattern of inheritance, though with lower lifetime risk of disease, a family history may not be apparent.

  • Differential diagnosis:

    • It is important to distinguish the multiorgan system syndromes that include breast or ovarian cancer as a single feature (ie, Cowden ...

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