Large family with both parents affected by distinct BRCA1 mutations: implications for genetic testing
- Anna P Sokolenko1,
- Dmitry A Voskresenskiy1,
- Aglaya G Iyevleva1,
- Elena M Bit-Sava1,
- Nadezhda I Gutkina2,
- Maxim S Anisimenko2,
- Nathalia Yu Sherina1,
- Nathalia V Mitiushkina1,
- Yulia M Ulibina1,
- Olga S Yatsuk1,
- Olga A Zaitseva1,
- Evgeny N Suspitsin1,
- Alexandr V Togo1,
- Valery A Pospelov3,
- Sergey P Kovalenko2,
- Vladimir F Semiglazov1 and
- Evgeny N Imyanitov1Email author
© Sokolenko et al; licensee BioMed Central Ltd. 2009
Received: 09 September 2008
Accepted: 26 January 2009
Published: 26 January 2009
Although the probability of both parents being affected by BRCA1 mutations is not negligible, such families have not been systematically described in the literature. Here we present a large breast-ovarian cancer family, where 3 sisters and 1 half-sister inherited maternal BRCA1 5382insC mutation while the remaining 2 sisters carried paternal BRCA1 1629delC allele. No BRCA1 homozygous mutations has been detected, that is consistent with the data on lethality of BRCA1 knockout mice. This report exemplifies that the identification of a single cancer-predisposing mutation within the index patient may not be sufficient in some circumstances. Ideally, all family members affected by breast or ovarian tumor disease have to be subjected to the DNA testing, and failure to detect the mutation in any of them calls for the search of the second cancer-associated allele.
BRCA1 and BRCA2 mutations occur in approximately 0.2–1% healthy subjects, 5% non-selected breast cancer (BC) patients, 15% consecutive ovarian cancer (OC) cases, and 25% females with clinical features of hereditary breast-ovarian cancer (HBOC) syndrome [1–8]. Given low populational frequency and high penetrance of deleterious BRCA1 and BRCA2 mutations, only one of the parent of the affected proband is usually suspected to contain this genetic lesion. Nevertheless, the probability of both parents being a carrier of BRCA1 or BRCA2 mutation is not negligible. If we consider random healthy couples, this estimate would be equal to 0.2–1% × 0.2–1% = 0.0004–0.01% (i.e., 1:250000 - 1:10000). This probability is significantly increased if we deal with already affected females. Indeed, the most conservative calculation would imply that the chance to detect a mutation in one of the parents of the patient is the same as in the patient herself, whereas the probability for the remaining parent to be affected by BRCA1 or BRCA2 defect is similar to the populational frequency of the latter. Therefore, approximately 0.01–0.05% (i.e., 1:10000 - 1:2000) of BC patients, 0.03 – 0.15% (i.e., 1:3333-1:667) of OC patients, and 0.05–0.25% (i.e., 1:2000 - 1:400) of women with HOBC have both parents carrying BRCA1 or BRCA2 mutation. Coincident occurrence of BRCA1 heterozygosity in mother and father is particularly likely if both parents of the patient report a strong family history of the breast-ovarian cancer disease, however these situations are exceptionally rare due to gender-specific penetrance of BRCA1 and BRCA2 alterations and lack of explicit information in the most of pedigrees.
Since 2 sisters from this family carry BRCA1 1629delC, it is highly unlikely that these mutations appeared de novo; instead, it is nearly certain that the father of these sisters (II.5) was a carrier of this allele. We could not validate this assumption, because this man died a long time ago. Similarly, patient III.11 was likely to carry BRCA1 5382insC mutation, but this could not be confirmed.
Homozygosity for BRCA1 inactivation was reported previously in a single human , although this observation was later suggested to be a technical artifact . We conducted testing for both BRCA1 5382insC and 1629delC alleles in all available DNA samples, and failed to detect any biallelic defect. Taken together with the only available publication on BRCA1 mutation occurring in both parents  and a large body of evidence for early embryonic lethality of BRCA1 knockout mice [12–14], our data provide additional support to the common statement on the lack of viability of BRCA1-null homozygotes. This contrasts to the situation with another breast-ovarian cancer gene, BRCA2, whose homozygous inactivation leads to Fanconi anemia but is not absolutely lethal .
While families harboring both BRCA1 and BRCA2 mutations have been repeatedly presented in the literature , there is no systematic analysis of the pedigrees with both parents carrying distinct alterations in the BRCA1 gene . Our observation calls for the same caution as was formulated in a series of articles describing double mutations for BRCA1 and BRCA2 . First, in the communities with strong founder effect, relaxed criteria for subjects selection should be used when considering the administration of appropriate non-expensive PCR tests; it is highly recommended that all BC and OC patients, and perhaps even healthy middle-aged females, have to be offered the opportunity of the DNA analysis [3, 6, 8, 16]. Secondly, the possibility of existence of disease phenocopies within the same family has to be always remembered; therefore, failure to identify breast-ovarian cancer gene mutation in the index case does not exclude the possibility of identification of BRCA defect in other affected members of a given pedigree. Ideally, all affected members of the family have to undergo DNA testing at least for the presence of founder mutations .
Written informed consent was obtained from the alive memebrs of the described family for the publication of this case report. Copies of the written consent are available for review by the Editor-in-Chief of this journal.
hereditary breast-ovarian cancer (HBOC) syndrome
This work is supported by INTAS (grant 05-1000008-7870), Russian Agency for Science and Innovations (grant 02.512.11.2101), Grant for Helmholtz-Russia Joint Research Groups (grant HRJRG-006/07-04-92282-à), Russian Foundation for Basic Research (grants 07-04-00122-à, 07-04-00172-à, 08-04-00369-à), and the Russian Academy of Sciences (grant "Molecular and Cell Biology"). We cordially thank Prof. Peter Devilee (Leiden University Medical Center, The Netherlands) for the fruitful discussion.
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