Effect of <Emphasis Type="Italic">BRCA2</Emphasis> sequence variants predicted to disrupt exonic splice enhancers on <Emphasis Type="Italic">BRCA2</Emphasis>transcripts

Background  

Genetic screening of breast cancer patients and their families have identified a number of variants of unknown clinical significance in the breast cancer susceptibility genes, BRCA1 and BRCA2. Evaluation of such unclassified variants may be assisted by web-based bioinformatic prediction tools, although accurate prediction of aberrant splicing by unclassified variants affecting exonic splice enhancers (ESEs) remains a challenge.     

A genome wide linkage search for breast cancer susceptibility genes

Mutations in known breast cancer susceptibility genes account for a minority of the familial aggregation of the disease. To search for further breast cancer susceptibility genes, we performed a combined analysis of four genome-wide linkage screens, which included a total of 149 multiple case breast cancer families. All families included at least three cases of breast cancer diagnosed below age 60 years, at least one of whom had been tested and found not to carry a BRCA1 or BRCA2 mutation. Evidence for linkage was assessed using parametric linkage analysis, assuming both a dominant and a recessive mode of inheritance, and using nonparametric methods. The highest LOD score obtained in any analysis of the combined data was 1.80 under the dominant model, in a region on chromosome 4 close to marker D4S392. Three further LOD scores over 1 were identified in the parametric analyses and two in the nonparametric analyses. A maximum LOD score of 2.40 was found on chromosome arm 2p in families with four or more cases of breast cancer diagnosed below age 50 years. The number of linkage peaks did not differ from the number expected by chance. These results suggest regions that may harbor novel breast cancer susceptibility genes. They also indicate that no single gene is likely to account for a large fraction of the familial aggregation of breast cancer that is not due to mutations in BRCA1 or BRCA2.     

Survival from breast cancer in women with a BRCA2 mutation by treatment

Background The impact of various breast-cancer treatments on patients with a BRCA2 mutation has not been studied. We sought to estimate the impact of bilateral oophorectomy and other treatments on breast cancer-specific survival among patients with a germline BRCA2 mutation.Methods We identified 664 women with stage I–III breast cancer and a BRCA2 mutation by combining five different datasets (retrospective and prospective). Subjects were followed for 7.2 years from diagnosis to death from breast cancer. Tumour characteristics and cancer treatments were patient-reported and derived from medical records. Predictors of survival were determined using Cox proportional hazard models, adjusted for other treatments and for prognostic features.Results The 10-year breast-cancer survival for ER-positive patients was 78.9% and for ER-negative patients was 82.3% (adjusted HR = 1.23 (95% CI, 0.62–2.45, p = 0.55)). The 10-year breast-cancer survival for women who had a bilateral oophorectomy was 89.1% and for women who did not have an oophorectomy was 59.0% (adjusted HR = 0.45; 95% CI, 0.28–0.72, p = 0.001). The adjusted hazard ratio for chemotherapy was 0.83 (95% CI, 0.65–1.53: p = 0.56).Conclusions For women with breast cancer and a germline BRCA2 mutation, positive ER status does not predict superior survival. Oophorectomy is associated with a reduced risk of death from breast cancer and should be considered in the treatment plan.Subject terms: Targeted therapies, Breast cancer     

Benign breast disease increases breast cancer risk independent of underlying familial risk profile: Findings from a Prospective Family Study Cohort

Benign breast disease (BBD) is an established breast cancer (BC) risk factor, but it is unclear whether the magnitude of the association applies to women at familial or genetic risk. This information is needed to improve BC risk assessment in clinical settings. Using the Prospective Family Study Cohort, we used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of BBD with BC risk. We also examined whether the association with BBD differed by underlying familial risk profile (FRP), calculated using absolute risk estimates from the Breast Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) model. During 176,756 person-years of follow-up (median: 10.9 years, maximum: 23.7) of 17,154 women unaffected with BC at baseline, we observed 968 incident cases of BC. A total of 4,704 (27%) women reported a history of BBD diagnosis at baseline. A history of BBD was associated with a greater risk of BC: HR = 1.31 (95% CI: 1.14–1.50), and did not differ by underlying FRP, with HRs of 1.35 (95% CI: 1.11–1.65), 1.26 (95% CI: 1.00–1.60), and 1.40 (95% CI: 1.01–1.93), for categories of full-lifetime BOADICEA score <20%, 20 to <35%, ≥35%, respectively. There was no difference in the association for women with BRCA1 mutations (HR: 1.64; 95% CI: 1.04–2.58), women with BRCA2 mutations (HR: 1.34; 95% CI: 0.78–2.3) or for women without a known BRCA1 or BRCA2 mutation (HR: 1.31; 95% CI: 1.13–1.53) (p_interaction = 0.95). Women with a history of BBD have an increased risk of BC that is independent of, and multiplies, their underlying familial and genetic risk.     

Predictors of the use of complementary and alternative medicine (CAM) by women at high risk for breast cancer

BackgroundFew data exist regarding the use of complementary and alternative medicine (CAM) by unaffected women at high risk of breast cancer.MethodsSelf-reported CAM use by women from multiple-case breast cancer families was obtained by questionnaire. Factors associated with CAM use were assessed using multiple logistic regression.ResultsOf 892 women, 55% (n = 489) used CAM, 6% (n = 53) specifically to prevent cancer. CAM use was independently associated with tertiary education level (OR 2.56, 95% CI 1.83–3.58, p < 0.001), greater physical activity (OR 1.05 per hour of physical activity/week, 95% CI 1.00–1.10, p = 0.049), greater anxiety (OR 1.92, 95% CI 1.16–3.16, p = 0.01), not currently smoking (OR 0.64, 95% CI 0.42–0.97, p = 0.037) and lower perceived BC risk (OR 0.82 per 20 percentage points, 95% CI 0.72–0.94, p = 0.005).ConclusionsThe majority of high-risk women use CAM, but mostly for reasons other than cancer prevention. Most predictors of CAM use are consistent with the limited literature for women at high risk for cancer.