Breast tumor characteristics of BRCA1 and BRCA2 gene mutation carriers on MRI.
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ABSTRACT:
SUBMITTER: Veltman J
PROVIDER: S-EPMC2292493 | biostudies-other | 2008 May
REPOSITORIES: biostudies-other
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Project description:PurposeBRCA1 and BRCA2 tumors exhibit different characteristics. This study aimed to assess and compare the ultrasound findings and pathologic features of BRCA1 and BRCA2 breast cancers. To our knowledge, this is the first study to examine the mass formation, vascularity, and elasticity in breast cancers of BRCA-positive Japanese women.MethodsWe identified patients with breast cancer harboring BRCA1 or BRCA2 mutations. After excluding patients who underwent chemotherapy or surgery before the ultrasound, we evaluated 89 cancers in BRCA1-positive and 83 in BRCA2-positive patients. The ultrasound images were reviewed by three radiologists in consensus. Imaging features, including vascularity and elasticity, were assessed. Pathological data, including tumor subtypes, were reviewed.ResultsSignificant differences in tumor morphology, peripheral features, posterior echoes, echogenic foci, and vascularity were observed between BRCA1 and BRCA2 tumors. BRCA1 breast cancers tended to be posteriorly accentuating and hypervascular. In contrast, BRCA2 tumors were less likely to form masses. In cases where a tumor formed a mass, it tended to show posterior attenuation, indistinct margins, and echogenic foci. In pathological comparisons, BRCA1 cancers tended to be triple-negative subtypes. In contrast, BRCA2 cancers tended to be luminal or luminal-human epidermal growth factor receptor 2 subtypes.ConclusionIn the surveillance of BRCA mutation carriers, radiologists should be aware that the morphological differences between tumors are quite different between BRCA1 and BRCA2 patients.
| S-EPMC10202977 | biostudies-literature
Project description:Multifocal (MF)/multicentric (MC) breast cancer is generally considered to be where two or more breast tumours are present within the same breast, and is seen in ~10% of breast cancer cases. This study investigates the prevalence of multifocality/multicentricity in a cohort of BRCA1/2 mutation carriers with breast cancer from Northern Ireland via cross-sectional analysis. Data from 211 women with BRCA1/2 mutations (BRCA1-91, BRCA2-120) and breast cancer were collected including age, tumour focality, size, type, grade and receptor profile. The prevalence of multifocality/multicentricity within this group was 25% but, within subgroups, prevalence amongst BRCA2 carriers was more than double that of BRCA1 carriers (p =?0.001). Women affected by MF/MC tumours had proportionately higher oestrogen receptor positivity (p =?0.001) and lower triple negativity (p =?0.004). These observations are likely to be driven by the higher BRCA2 mutation prevalence observed within this cohort. The odds of a BRCA2 carrier developing MF/MC cancer were almost four-fold higher than a BRCA1 carrier (odds ratio: 3.71, CI: 1.77-7.78, p =?0.001). These findings were subsequently validated in a second, large independent cohort of patients with BRCA-associated breast cancers from a UK-wide multicentre study. This confirmed a significantly higher prevalence of MF/MC tumours amongst BRCA2 mutation carriers compared with BRCA1 mutation carriers. This has important implications for clinicians involved in the treatment of BRCA2-associated breast cancer, both in the diagnostic process, in ensuring that tumour focality is adequately assessed to facilitate treatment decision-making, and for breast surgeons, particularly if breast conserving surgery is being considered as a treatment option for these patients.
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Project description:Breast cancer (BC) prognosis in BRCA1 and BRCA2 mutation carriers has been reported contradictorily, and the significance of variables influencing prognosis in sporadic BC is not established in BC patients with hereditary BRCA1/BRCA2 mutations. In this retrospective cohort study, we analyzed the effect of clinicopathological characteristics on BC prognosis (disease-free survival [DFS] and disease-specific survival [DSS]) in hereditary BRCA1/BRCA2 mutation carriers. We enrolled 234 BRCA1/BRCA2 mutation carriers and 899 non-carriers, of whom 191 carriers and 680 non-carriers, with complete data, were available for survival analyses. We found that patients with ER-positive tumors developed disease recurrence 2.3-times more likely when they carried a BRCA1/BRCA2 mutation (23/60; 38.3% ER-positive carriers vs. 74/445; 16.6% ER-positive non-carriers; p < 0.001). ER-positive mutation carriers also had a 3.4-times higher risk of death due to BC compared with ER-positive non-carriers (13/60; 21.7% vs. 28/445; 6.3%; p < 0.001). Moreover, prognosis in ER-negative BRCA1/BRCA2 mutation carriers was comparable with that in ER-positive non-carriers. Our study demonstrates that ER-positivity worsens BC prognosis in BRCA1/BRCA2 mutation carriers, while prognosis for carriers with ER-negative tumors (including early-onset) is significantly better and comparable with that in ER-positive, older BC non-carriers. These observations indicate that BRCA1/BRCA2 mutation carriers with ER-positive BC represent high-risk patients.
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Project description:BackgroundIt is unknown whether a history of breast cancer (BC) affects the outcome of BRCA1/2-associated epithelial ovarian cancer (EOC). This was investigated in the current analysis.MethodsWe included 386 BRCA1/2-associated EOC patients diagnosed between 1980 and 2015. Progression-free survival (PFS), progression-free interval (PFI), overall survival (OS) and ovarian cancer-specific survival (OCSS) were compared between EOC patients with and without previous BC.ResultsBRCA-associated EOC patients with, vs without, a BC history had a significantly worse PFS and PFI (multivariate hazard ratio (HRmult) 1.47; 95% confidence interval (CI) 1.03-2.08 and HRmult 1.43; 95% CI 1.01-2.03), and a non-significantly worse OS (HRmult 1.15; 95% CI 0.84-1.57) and OCSS (HRmult 1.18; 95% CI 0.85-1.62). Ovarian cancer-specific survival was significantly worse for the subgroup treated with adjuvant chemotherapy for BC (HRmult 1.99; 95% CI 1.21-3.31).ConclusionsOur results suggest that BRCA1/2-associated EOC patients with a previous BC have a worse outcome than EOC patients without BC, especially when treated with adjuvant chemotherapy.
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Project description:Early genetic changes during cancer initiation may provide targets for agents that delay, or even prevent, cancer. We hypothesized that cells bearing a single inherited “hit” in a tumor suppressor gene express an altered mRNA repertoire that may identify targets for measures that could delay or even prevent progression to carcinoma. Here, we report on the transcriptomes of primary breast and ovarian epithelial cells cultured from BRCA1 and BRCA2 mutation-carriers and controls. Our comparison analyses identified multiple changes in gene expression, in both tissues for both mutations that were independently validated by real-time RT-PCR analysis. Several of the differentially expressed genes had been previously proposed as cancer markers including, mammaglobin in breast cancer and serum amyloid in ovarian cancer. These findings demonstrate that heterozygosity for a mutant tumor suppressor gene can alter the expression profiles of phenotypically normal epithelial cells in a gene-specific manner, and that these detectable effects of “one-hit” represent early molecular changes in tumorigenesis that may serve as novel biomarkers of cancer risk and as targets for chemoprevention Using affymetrix U133 plus2 chips, we compare the transcriptome of primary breast and ovarian epithelial cultures derived from subjects predisposed to cancer, bearing monoallelic BRCA1 or BRCA2 mutations, with corresponding cultures from control individuals that do not have mutations. For both breast and ovarian samples, epithelial cell cultures were generated from 6 subjects that have both BRCA1 or BRCA2 mutations and 6 subjects that do not have mutations. Affymetrix U133 plus 2 chips were used to profile the transcriptome of BRCA1 or BRCA2 mutant and wild type. In total 36 chips were used to profile 18 samples from both breast and ovary, 6 mutant (BRCA1 and BRCA2) and 6 wild type.
| S-ECPF-GEOD-19383 | biostudies-other
Project description:Pathogenic germline mutations in BRCA1 or BRCA2 are detected in less than one third of families with a strong history of breast cancer. It is therefore expected that mutations still remain undetected by currently used screening methods. In addition, a growing number of BRCA1/2 sequence variants of unclear pathogen significance are found in the families, constituting an increasing clinical challenge. New methods are therefore needed to improve the detection rate and aid the interpretation of the clinically uncertain variants. In this study we analyzed a series of 33 BRCA1, 22 BRCA2, and 128 sporadic tumors by RNA profiling to investigate the classification potential of RNA profiles to predict BRCA1/2 mutation status. We found that breast tumors from BRCA1 and BRCA2 mutation carriers display characteristic RNA expression patterns, allowing them to be distinguished from sporadic tumors. The majority of BRCA1 tumors were basal-like while BRCA2 tumors were mainly luminal B. Using RNA profiles, we were able to distinguish BRCA1 tumors from sporadic tumors among basal-like tumors with 83% accuracy and BRCA2 from sporadic tumors among luminal B tumors with 89% accuracy. Furthermore, subtype-specific BRCA1/2 gene signatures were successfully validated in two independent data sets with high accuracies. Although additional validation studies are required, indication of BRCA1/2 involvement ("BRCAness") by RNA profiling could potentially be valuable as a tool for distinguishing pathogenic mutations from benign variants, for identification of undetected mutation carriers, and for selecting patients sensitive to new therapeutics such as PARP inhibitors.
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Project description:BACKGROUND:The outcomes of sporadic pancreatic ductal adenocarcinoma (PDAC) patients with germline mutations of BRCA1/BRCA2 remains unclear. The prognostic significance of BRCA1/BRCA2 mutations on survival is not well established. STUDY DESIGN:We performed targeted next-generation sequencing (NGS) to identify BRCA1/BRCA2 germline mutations in resected sporadic PDAC cases from 2000 to 2015. Germline BRCA mutation carriers were matched by age and tumor location to those with BRCA1/BRCA2 wild-type genes from our institutional database. Demographics, clinicopathologic features, overall survival (OS), and disease-free survival (DFS) were abstracted from medical records and compared between the 2 cohorts. RESULTS:Twenty-two patients with sporadic cancer and BRCA1 (n = 4) or BRCA2 (n = 18) germline mutations and 105 wild-type patients were identified for this case-control study. The BRCA1/BRCA2 mutations were associated with inferior median OS (20.2 vs 27.8 months, p = 0.034) and DFS (8.4 vs 16.7 months, p < 0.001) when compared with the matched wild-type controls. On multivariable analyses, a BRCA1/BRCA2 mutation (hazard ratio [HR] 2.10, p < 0.001), positive margin status (HR 1.72, p = 0.021), and lack of adjuvant therapy (HR 2.38, p < 0.001), were all independently associated with worse survival. Within the BRCA1/BRCA2 mutated group, having had platinum-based adjuvant chemotherapy (n = 10) was associated with better survival than alternative chemotherapy (n = 8) or no adjuvant therapy (n = 4) (31.0 vs 17.8 vs 9.3 months, respectively, p < 0.001). CONCLUSIONS:Carriers of BRCA1/BRCA2 mutation with sporadic PDAC had a worse survival after pancreatectomy than their BRCA wild-type counterparts. However, platinum-based chemotherapy regimens were associated with markedly improved survival in patients with BRCA1/BRCA2 mutations, with survival differences no longer appreciated with wild-type patients.
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Project description:Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range linkage disequilibrium (LD) resulting from a selective sweep, although genetic drift in a founder population may also act to create long-distance LD. To date, few studies have used the tools of statistical genomics to examine the likelihood of long-range LD at a deleterious locus in a population that faced a genetic bottleneck. We studied the genotypes of hundreds of women from a large international consortium of BRCA1 and BRCA2 mutation carriers and found that AJ women exhibited long-range haplotypes compared to CNJ women. More than 50% of the AJ chromosomes with the BRCA1 185delAG mutation share an identical 2.1 Mb haplotype and nearly 16% of AJ chromosomes carrying the BRCA2 6174delT mutation share a 1.4 Mb haplotype. Simulations based on the best inference of Ashkenazi population demography indicate that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype blocks observed at high frequency in the BRCA1 and BRCA2 regions of Ashkenazi Jews.
| S-EPMC3196382 | biostudies-literature
Project description:To evaluate the effect of the cumulative number of ovulatory cycles and its contributing components on the risk of breast cancer among BRCA mutation carriers.We conducted a matched case-control study on 2,854 pairs of women with a BRCA1 or BRCA2 mutation. Conditional logistic regression was used to estimate the association between the number of ovulatory cycles and various exposures and the risk of breast cancer. Information from a subset of these women enrolled in a prospective cohort study was used to calculate age-specific breast cancer rates.The annual risk of breast cancer decreased with the number of ovulatory cycles experienced (? = -0.69; P = 0.03). Age at menarche and duration of breastfeeding were inversely related with risk of breast cancer among BRCA1 (P(trend) < 0.0001) but not among BRCA2 (P(trend) ? 0.28) mutation carriers. The reduction in breast cancer risk associated with surgical menopause [OR, 0.52; 95% confidence interval (CI), 0.40-0.66; P(trend) < 0.0001] was greater than that associated with natural menopause (OR, 0.81; 95% CI, 0.62-1.07; P(trend) = 0.14). There was a highly significant reduction in breast cancer risk among women who had an oophorectomy after natural menopause (OR, 0.13; 95% CI, 0.02-0.54; P = 0.006).These data challenge the hypothesis that breast cancer risk can be predicted by the lifetime number of ovulatory cycles in women with a BRCA mutation. Both pre- and postmenopausal oophorectomy protect against breast cancer.Understanding the basis for the protective effect of oophorectomy has important implications for chemoprevention.
| S-EPMC3593267 | biostudies-literature
Project description:PurposeUnaffected women who carry BRCA1 or BRCA2 mutations face difficult choices about reducing their breast cancer risk. Understanding their treatment preferences could help us improve patient counseling and inform drug trials. The objective was to explore preferences for various risk-reducing options among women with germline BRCA1/2 mutations using a discrete-choice experiment survey and to compare expressed preferences with actual behaviors.MethodsA discrete-choice experiment survey was designed wherein women choose between hypothetical treatments to reduce breast cancer risk. The hypothetical treatments were characterized by the extent of breast cancer risk reduction, treatment duration, impact on fertility, hormone levels, risk of uterine cancer, and ease and mode of administration. Data were analyzed using a random-parameters logit model. Women were also asked to express their preference between surgical and chemoprevention options and to report on their actual risk-reduction actions. Women aged 25-55 years with germline BRCA1/2 mutations who were unaffected with breast or ovarian cancer were recruited through research registries at five clinics and a patient advocacy group.ResultsBetween January 2015 and March 2016, 622 women completed the survey. Breast cancer risk reduction was the most important consideration expressed, followed by maintaining fertility. Among the subset of women who wished to have children in future, the ability to maintain fertility was the most important factor, followed by the extent of risk reduction. Many more women said they would take a chemoprevention drug than had actually taken chemoprevention.ConclusionsWomen with BRCA1/2 mutations indicated strong preferences for breast cancer risk reduction and maintaining fertility. The expressed desire to have a safe chemoprevention drug available to them was not met by current chemoprevention options.
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