Uncertainty exists whether the 4154delA mutation of the BRCA1 gene detected in unrelated individuals from Latvia, Poland and Russia is a founder mutation with a common ancestral origin. To trace back this problem we analysed the mutation-associated haplotype of the BRCA1 intragenic SNPs as well as intragenic and nearby STR markers in mutation carriers from the aforementioned populations. The mutation-associated SNP alleles were found to be "T-A-A-A-A-G" for six intragenic SNPs of the BRCA1 gene (IVS8-58delT, 3232A/G, 3667A/G, IVS16-68A/G, IVS16-92A/G, IVS18+66G/A, respectively). The alleles 195, 154, 210 and 181 were found to be associated with the 4154delA mutation for STR markers D17S1325, D17S855, D17S1328 and D17S1320, correspondingly. Further analysis of markers in the 4154delA mutation carriers from all three populations allows us to assert that all analysed mutation carriers share a common ancestry.
Social, ethical and policy analysis of the issues arising from gene patenting and commercial genetic testing is enhanced by the application of science and technology studies, and Actor-Network Theory (ANT) in particular. We suggest the potential for transferring ANT's flexible nature to an applied heuristic methodology for gathering empirical information and for analysing the complex networks involved in the development of genetic technologies. Three concepts are explored in this paper--actor-networks, translation, and drift--and applied to the case of Myriad Genetics and their commercial BRACAnalysis genetic susceptibility test for hereditary breast cancer. Treating this test as an active participant in socio-technical networks clarifies the extent to which it interacts with, shapes and is shaped by people, other technologies, and institutions. Such an understanding enables more sophisticated and nuanced technology assessment, academic analysis, as well as public debate about the social, ethical and policy implications of the commercialization of new genetic technologies.
We hypothesized that the transcriptome of primary cultures of morphologically normal ovarian surface epithelial cells could be altered by the presence of a heterozygous BRCA1 or BRCA2 mutation. We aimed to discover early events associated with ovarian carcinogenesis, which could represent putative targets for preventive strategies of this silent killer tumor. We identified the first molecular signature associated with French Canadian BRCA1 or BRCA2 founder mutations in morphologically normal ovarian epithelial cells. We discovered that wild-type and mutated BRCA2 allelic transcripts were expressed not only in morphologically normal but also in tumor cells from BRCA2-8765delAG carriers. Further analysis of morphologically normal ovarian and tumor cells from BRCA1-4446C>T carriers lead to the same observation. Our data support the idea that one single hit in BRCA1 or BRCA2 is sufficient to alter the transcriptome of phenotypically normal ovarian epithelial cells. The highest level of BRCA2-mutated allele transcript expression was measured in cells originating from the most aggressive ovarian tumor. The penetrance of the mutation and the aggressiveness of the related tumor could depend on a dosage effect of the mutated allele transcript.
ZNF350/ZBRK1 is a transcription factor, which associates with BRCA1 to co-repress GADD45A to regulate DNA damage repair, and the expression of ZNF350 is altered in different human carcinomas. In a previous study, we identified ZNF350 genomic variants potentially involved in breast cancer susceptibility in high-risk non-BRCA1/2 breast cancer individuals, which pointed toward a potential association for variants in the 5'-UTR and promoter regions. Therefore, direct sequencing was undertaken and identified 12 promoter variants, whereas haplotype analyses put in evidence four common haplotypes with a frequency>2%. However, based on their frequency observed in breast cancer and unrelated healthy individuals, these are not statistically associated with breast cancer risk. Luciferase promoter assays in two breast cancer cell lines identified two haplotypes (H11 and H12) stimulating significantly the expression of ZNF350 transcript compared with the common haplotype H8. The high expression of the H11 allele was associated with the variant c.-874A. Using MatInspector and Transcription Element Search softwares, in silico analyses predicted that the variant c.-874A created a binding site for the factors c-Myc and myogenin. This study represents the first characterization step of the ZNF350 promoter. Additional studies in larger cohorts and other populations will be needed to further evaluate whether common and/or rare ZNF350 promoter variants and haplotypes could be associated with a modest risk of breast cancer.
To determine whether autoimmune hypothyroidism (AIHT) influences breast cancer (BRCA) incidence or all-cause survival.
Administrative data were used to identify elderly women living in Ontario, Canada with and without AIHT based on prescriptions for levothyroxine (LT4) (N = 178,186). Women were followed from April 1, 1994-March 31, 2003 for BRCA outcomes.
The incidence of BRCA was similar in LT4 users and a propensity-matched cohort of non-users (adjusted HR = 0.99; 95% CI: 0.92-1.07). All-cause mortality was significantly lower in LT4 users compared to non-users (HR 0.95; 95% CI: 0.93-0.97, P
Women who carry a BRCA1 or BRCA2 gene mutation face a risk of developing breast or ovarian cancer at an earlier age than women without such a mutation. Relatively little is known about the psychosocial consequences-especially regarding marriage and childbearing-in young women who test positive for one of these mutations.
In 2006, participants were recruited from Web sites for women with breast cancer or BRCA gene mutations. Forty-four women ages 18 to 39 from 22 states and Canada who had had genetic testing and were found to carry a BRCA mutation were interviewed by phone or e-mail. A qualitative, grounded theory analysis was performed on the data, focusing on the participants' being young and having had genetic testing for the BRCA mutation. The findings reported here focus on three characteristics of the participants-whether or not they were married, had children, or had a breast cancer diagnosis-and how those characteristics were affected by the women's knowledge of their genetic risk.
Among the 13 unmarried participants, issues of when to disclose information about their genetic risk in intimate relationships were discussed. Many of the 24 participants who had children reported "staying alive" for their children as a primary goal; the childless women reported an urgency to have children. Of the 21 who had a breast cancer diagnosis, the youngest was 24 years old, and several said knowledge of their genetic risk influenced their decision to have the unaffected breast removed prophylactically.
A sense of being different and not understood was expressed in these interviews. These findings suggest that nurses should be aware of psychosocial issues, especially those surrounding marriage and childbearing, in their interactions with young women who carry a BRCA1 or BRCA2 gene mutation.
A recent addition to the debate about the benefits and harms of direct-to-consumer (DTC) advertising of medicines and pharmaceuticals is a growing critique of DTC marketing and sale of genetic tests. Academic and policy literatures exploring this issue have, however, tended to focus on the sale of genetic tests, paying rather less attention to the particular implications of advertising. The globalization of broadcast media and ever increasing access to the Internet mean that public exposure to advertising for medical technologies is a reality that national regulatory bodies will be hard pressed to constrain. Working through a case study detailing Myriad Genetics' 2002 pilot advertising campaign for their BRACAnalysis genetic susceptibility test for hereditary breast and ovarian cancer, this paper highlights some of the diverse and often overlooked and unregulated approaches to DTC advertising, and the associated social, ethical and policy implications.
This study attempted a national inventory of all bilateral prophylactic mastectomies performed in Sweden between 1995 and 2005 in high-risk women without a previous breast malignancy. The primary aim was to investigate the breast cancer incidence after surgery. Secondary aims were to describe the preoperative risk assessment, operation techniques, complications, histopathological findings, and regional differences.
Geneticists, oncologists and surgeons performing prophylactic breast surgery were asked to identify all women eligible for inclusion in their region. The medical records were reviewed in each region and the data were analyzed centrally. The BOADICEA risk assessment model was used to calculate the number of expected/prevented breast cancers during the follow-up period.
A total of 223 women operated on in 8 hospitals were identified. During a mean follow-up of 6.6 years, no primary breast cancer was observed compared with 12 expected cases. However, 1 woman succumbed 9 years post mastectomy to widespread adenocarcinoma of uncertain origin. Median age at operation was 40 years. A total of 58% were BRCA1/2 mutation carriers. All but 3 women underwent breast reconstruction, 208 with implants and 12 with autologous tissue. Four small, unifocal, invasive cancers and 4 ductal carcinoma in situ were found in the mastectomy specimens. The incidence of nonbreast related complications was low (3%). Implant loss due to infection/necrosis occurred in 21 women (10%) but a majority received a new implant later. In total, 64% of the women underwent at least 1unanticipated secondary operation.
Bilateral prophylactic mastectomy is safe and efficacious in reducing future breast cancer in asymptomatic women at high risk. Unanticipated reoperations are common. Given the small number of patients centralization seems justified.
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.
Several genetic risk models for breast and ovarian cancer have been developed, but their applicability to specific populations has not been evaluated. We used data from French-Canadian families to evaluate the mutation predictions given by the BRCAPRO and BOADICEA models. We also used this data set to estimate the age-specific risks for breast and ovarian cancer in BRCA1 and BRCA2 mutation carriers.
A total of 195 families with multiple affected individuals with breast or ovarian cancer were recruited through the INHERIT (INterdisciplinary HEalth Research International Team on BReast CAncer susceptibility) BRCAs research program. Observed BRCA1 and BRCA2 mutation status was compared with predicted carrier probabilities under the BOADICEA and BRCAPRO models. The models were assessed using Brier scores, attributes diagrams and receiver operating characteristic curves. Log relative risks for breast and ovarian cancer in mutation carriers versus population risks were estimated by maximum likelihood, using a modified segregation analysis implemented in the computer program MENDEL. Twenty-five families were eligible for inclusion in the BRCA1 penetrance analysis and 27 families were eligible for the BRCA2 penetrance analysis.
The BOADICEA model predicted accurately the number of BRCA1 and BRCA2 mutations for the various groups of families, and was found to discriminate well at the individual level between carriers and noncarriers. BRCAPRO over-predicted the number of mutations in almost all groups of families, in particular the number of BRCA1 mutations. It significantly overestimated the carrier frequency for high predicted probabilities. However, it discriminated well between carriers and noncarriers. Receiver operating characteristic (ROC) curves indicate similar sensitivity and specificity for BRCAPRO and BOADICEA. The estimated risks for breast and ovarian cancer in BRCA1 and BRCA2 mutation carriers were consistent with previously published estimates.
The BOADICEA model predicts accurately the carrier probabilities in French-Canadian families and may be used for counselling in this population. None of the penetrance estimates was significantly different from previous estimates, suggesting that previous estimates may be appropriate for counselling in this population.