BRCA1 and BRCA2 mutation analysis of 208 Ashkenazi Jewish women with ovarian cancer

Abstract

Ovarian cancer is a component of the autosomal-dominant hereditary breast-ovarian cancer syndrome and may be due to a mutation in either the BRCA1 or BRCA2 genes. Two mutations in BRCA1 (185delAG and 5382insC) and one mutation in BRCA2 (6174delT) are common in the Ashkenazi Jewish population. One of these three mutations is present in approximately 2% of the Jewish population. Each mutation is associated with an increased risk of ovarian cancer, and it is expected that a significant proportion of Jewish women with ovarian cancer will carry one of these mutations. To estimate the proportion of ovarian cancers attributable to founding mutations in BRCA1 and BRCA2 in the Jewish population and the familial cancer risks associated with each, we interviewed 213 Jewish women with ovarian cancer at 11 medical centers in North America and Israel and offered these women genetic testing for the three founder mutations. To establish the presence of nonfounder mutations in this population, we also completed the protein-truncation test on exon 11 of BRCA1 and exons 10 and 11 of BRCA2. We obtained a detailed family history on all women we studied who had cancer and on a control population of 386 Ashkenazi Jewish women without ovarian or breast cancer. A founder mutation was present in 41.3% of the women we studied. The cumulative incidence of ovarian cancer to age 75 years was found to be 6.3% for female first-degree relatives of the patients with ovarian cancer, compared with 2.0% for the female relatives of healthy controls (relative risk 3.2; 95% CI 1.5-6.8; P=.002). The relative risk to age 75 years for breast cancer among the female first-degree relatives was 2.0 (95% CI 1.4-3.0; P=.0001). Only one nonfounder mutation was identified (in this instance, in a woman of mixed ancestry), and the three founding mutations accounted for most of the observed excess risk of ovarian and breast cancer in relatives.

Figure 1

Cumulative incidence of ovarian cancer to age 75 years in female first-degree relatives of women with cancer and control women. We observed 20 ovarian cancers among the 638 female relatives of women with ovarian cancer and 10 ovarian cancers among the 1,130 female relatives of control women (P=.0015).

Figure 2

Cumulative incidence of breast cancer to age 75 years in female first-degree relatives of women with cancer and control women. We observed 63 breast cancers among the 638 female relatives of cases with ovarian cancer and 50 breast cancers among the 1,130 female relatives of control women (P<.0001).

Figure 3

Cumulative incidence of ovarian cancer to age 75 years in female first-degree relatives of carriers, noncarriers, and controls. We observed 13 ovarian cancers among the 253 female relatives of carrier women with ovarian cancer, 7 ovarian cancers among the 368 female relatives of noncarrier cases, and 10 ovarian cancers among the 1,130 female relatives of control women (P<.0001).

Figure 4

Cumulative incidence of breast cancer to age 75 years in female first-degree relatives of carriers, noncarriers, and controls. We observed 36 breast cancers among the 253 female relatives of carrier women with ovarian cancer, 27 breast cancers among the 368 female relatives of noncarrier women, and 50 ovarian cancers among the 1,130 female relatives of control women (P<.0001).

Figure 5

Cumulative incidence of breast cancer to age 75 years in female first-degree relatives of women with serous and nonserous ovarian cancer and control women. We observed 37 breast cancers among the 305 female relatives of women with serous ovarian cancer, 9 breast cancers among the 141 female relatives of women with nonserous ovarian cancer, and 50 ovarian cancers among the 1,130 female relatives of control women (P<.0001).

Figure 6

Pedigree of the family carrying the 6696delTC mutation. Circles denote women; squares denote men. Individuals affected with cancer (blackened symbols) and unaffected individuals (unblackened symbols) are both indicated. A diagonal line through a symbol indicates that the individual denoted is dead.