According to the results of a study published in the Journal of the American Medical Association, the likelihood that a young breast cancer patient with no family history of the disease carries a BRCA1 or BRCA2 mutation varies by the number of older female relatives on both her father’s and her mother’s sides of the family. Available BRCA risk prediction models may underestimate risk among women with few older female relatives.

Inherited mutations in two genes-BRCA1 and BRCA2-have been found to greatly increase the lifetime risk of developing breast and ovarian cancer. Mutations in these genes can be passed down through either the mother’s or the father’s side of the family.

Although BRCA1/2 testing is not recommended for all women, testing may benefit women at increased risk of carrying a mutation. Risk of a BRCA1 or BRCA2 mutation is increased among women with a personal or family history of breast cancer at a young age, more than one cancer in the same person (for example cancer in both breasts or breast and ovarian cancer), a family history of both breast and ovarian cancer, or male breast cancer. In addition, women of Ashkenazi Jewish descent are more likely than other women to have a BRCA1 or BRCA2 mutation.

Several of these characteristics are incorporated into risk prediction models such as BRCAPRO, Myriad, and Couch. The risk prediction models estimate a woman’s risk of carrying a BRCA1 or BRCA2 mutation, and can help guide decisions about the need for genetic testing.

A limitation of available risk prediction models is that they may not function well when women have few close female relatives on either their mother’s side, their father’s side, or both. The absence of a family history of breast or ovarian cancer is less meaningful when there are few female relatives.

To evaluate how family size influences risk prediction accuracy, researchers conducted a study among 306 women being seen at high-risk clinics for genetic cancer risk assessment. The study was restricted to women who had developed breast cancer at an early age (before age 50), and who did not have any first- or second-degree relatives with breast or ovarian cancer.

Family structure was defined as limited if a woman had fewer than two first- or second-degree female relatives who lived past the age of 45 on her mother’s side, her father’s side, or both. First-degree relatives are parents, siblings, and children. Second-degree relatives are grandparents, grandchildren, uncles, aunts, nephews, nieces, and half-siblings

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Half the women had a limited family structure. A limited family structure was more common on the father’s side of the family than on the mother’s side of the family.

  • BRCA1 or BRCA2 mutations were identified in 13.7% of women with a limited family structure and 5.2% of women with an adequate family structure.
  • The available risk prediction models tended to overestimate risk among women with adequate family structure and to underestimate risk among women with a limited family structure.

These results suggest that consideration of the number of female relatives on both sides of the family (the mother’s and the father’s) may need to be taken into account when estimating a woman’s risk of carrying a BRCA1 or BRCA2 mutation. The absence of a family history of breast or ovarian cancer is less reassuring among women with few female relatives.

The researchers note, “…our findings support BRCA gene mutation testing for women with early onset breast cancer when the results will influence medical management, regardless of mutation estimates from existing models.”

The decision about whether or not to be tested is complex, and women who are considering testing are encouraged to discuss their situation with a genetic counselor.

Reference: Weitzel JN, Lagos VI, Cullinane CA. Limited family structure and BRCA gene mutation status in single cases of breast cancer. JAMA. 2007;2587-2595.

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