ABSTRACT: The Lifetime Risks of Breast Cancer in Ashkenazi Jewish
Carriers of BRCA1 and BRCA2 Mutations
Several studies using families with multiple occurrences of breast
cancer have provided evidence for a very high lifetime penetrance
in carriers of BRCA1 or BRCA2 mutations.
However, there are reasons
to suspect that the estimates of penetrance from studies of cancer
families may be inflated. Access to the genotypes of incident
cases of breast cancer in three hospitals and from a large series
of unaffected survey participants provided the basis for direct
estimation of the age-specific relative risks attributable to
these mutations, and the resulting lifetime penetrance, without
any reference to familial aggregation of cancer.
Cases were identified
from incident series of Jewish patients treated for primary breast
cancer at the three hospitals. Control data were obtained from
the large series of Jewish women recruited in the Washington,
D.C., area by investigators at the National Cancer Institute
and limited to 3434 women with no previous history of breast
or ovarian cancer.
All subjects were genotyped for the three
mutations that are relatively common in Ashkenazi Jews, namely
185delAG and 5382 insC in BRCA1 and 6174delT in BRCA2. For BRCA1,
the relative risks of breast cancer were estimated to be 21.6
in women under 40 years of age, 9.6 in women 40-49 years
of age, and 7.6 in women 50 years of age. On the basis of these
estimates, the penetrance of breast cancer at age 70 among BRCA1
mutation carriers is estimated to be 46% (95% confidence, 31%-80%)
rising to 59% (95% confidence, 40%-93%) at age 80. For BRCA2,
the relative risks in the same three age categories were estimated
to be 3.3, 3.3, and 4.6, respectively, resulting in a penetrance
at age 70 of 26% (95% confidence, 14%-50%) rising to 38%
(95% confidence, 20%-68%) at age 80.
The lifetime risk of
breast cancer in Jewish women who are mutation carriers estimated
via this approach is substantially lower than the reported lifetime
risks estimated using multiple-case families.
The risks appear
to be different for carriers of BRCA1 and BRCA2 mutations.
[05/18/2001; Cancer Epidemiology, Biomarkers and Prevention]
Science Magazine, 10/24/03
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