BRCA1 1675delA and 1135insA Account for One Third of Norwegian
Familial Breast-Ovarian Cancer and Are Associated with Later Disease Onset than
Less Frequent Mutations
Affiliations: Department of Oncology, University Hospital, SE-221 85
Lund, Sweden | Unit of Medical Genetics, The Norwegian Radium
Hospital, N-0310 Oslo, Norway | Department of Tumour Biology, The Norwegian Radium
Hospital, N-0310 Oslo, Norway
Note: [] Correspondence: Pål Møller, Unit of Medical
Genetics, The Norwegian Radium Hospital, N-0310 Oslo, Norway, Tel.: + 47 229
35675, Fax: + 47 229 35219, E-mail: pmoller@ulrik.uio.no
Abstract: A total of 845 women from breast-ovarian cancer kindreds were
enrolled in a clinical follow-up program for early disease diagnosis; 35 women
were prospectively identified with cancer. In order to estimate the role of
genetic factors for cancer predisposition in this well-defined set of patients,
considered as representative for familial breast-ovarian cancer in the
Norwegian population, the BRCA1 gene was investigated for germline mutations.
The entire coding region of BRCA1 was analysed using a protein truncation test,
direct sequencing and a screen for known large genomic deletions and
insertions. Twenty one (60%) of the 35 patients were identified as carriers of
11 distinct BRCA1 mutations. Two previously described founder mutations,
1675delA and 1135insA, were found to account for more than half (11/21) of all
BRCA1 cases and for almost one third (11/35) of all breast and ovarian cancers.
Supported by a previous population-based analysis of these founder mutations in
ovarian cancer, our findings suggest that a significant proportion of women at
risk for developing inherited breast and ovarian cancer can be identified. This
is particularly obvious in certain geographic regions where these founder
mutations are prevalent. Women carrying the two founder mutations had a
significantly older age of disease onset as compared to women with other BRCA1
mutations. This observation indicates that BRCA mutation penetrance estimates
from populations with strong founder effects may be biased. One reason why some
deleterious mutations are allowed to prevail in a population may be coupled to
penetrance and the fact that they seldom induce disease in women in
child-bearing ages. Eleven out of 12 (92%) breast cancers in BRCA1 mutation
carriers were estrogen receptor negative, versus 4 out of 9 (44%) in mutation
negative patients (p = 0.03). Histopathological characteristics of
the prospectively detected cancers indicated an unfavourable prognosis in
mutation carriers.
