Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

The Influence of Number and Timing of Pregnancies on Breast Cancer Risk for Women With BRCA1 or BRCA2 Mutations

Background: Full-term pregnancy (FTP) is associated with a reduced breast cancer (BC) risk over time, but women are at increased BC risk in the immediate years following an FTP. No large prospective studies, however, have examined whether the number and timing of pregnancies are associated with BC risk for BRCA1 and BRCA2 mutation carriers. Methods: Using weighted and time-varying Cox proportional hazards models, we investigated whether reproductive events are associated with BC risk for mutation carriers using a retrospective cohort (5707 BRCA1 and 3525 BRCA2 mutation carriers) and a prospective cohort (2276 BRCA1 and 1610 BRCA2 mutation carriers), separately for each cohort and the combined prospective and retrospective cohort. Results: For BRCA1 mutation carriers, there was no overall association with parity compared with nulliparity (combined hazard ratio [HRc] ¼ 0.99, 95% confidence interval [CI] ¼ 0.83 to 1.18). Relative to being uniparous, an increased number of FTPs was associated with decreased BC risk (HRc¼ 0.79, 95% CI ¼ 0.69 to 0.91; HRc¼ 0.70, 95% CI ¼ 0.59 to 0.82; HRc¼ 0.50, 95% CI ¼ 0.40 to 0.63, for 2, 3, and 4 FTPs, respectively, Ptrend < .0001) and increasing duration of breastfeeding was associated with decreased BC risk (combined cohort Ptrend ¼ .0003). Relative to being nulliparous, uniparous BRCA1 mutation carriers were at increased BC risk in the prospective analysis (prospective hazard ration [HRp] ¼ 1.69, 95% CI ¼ 1.09 to 2.62). For BRCA2 mutation carriers, being parous was associated with a 30% increase in BC risk (HRc ¼ 1.33, 95% CI ¼ 1.05 to 1.69), and there was no apparent decrease in risk associated with multiparity except for having at least 4 FTPs vs. 1 FTP (HRc¼ 0.72, 95% CI ¼ 0.54 to 0.98). Conclusions: These findings suggest differential associations with parity between BRCA1 and BRCA2 mutation carriers with higher risk for uniparous BRCA1 carriers and parous BRCA2 carriers

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Borstsparende therapie en mastectomie vergeleken: overleving na borstkanker in een vroeg stadium

Background Investigators of registry-based studies report improved survival for breast-conserving surgery plus radiotherapy compared with mastectomy in early breast cancer. As these studies did not present long-term overall and breast cancer-specific survival, the effect of breast-conserving surgery plus radiotherapy might be overestimated. In this study, we aimed to evaluate 10 year overall and breast cancer-specific survival after breast-conserving surgery plus radiotherapy compared with mastectomy in Dutch women with early breast cancer. Methods In this population-based study, we selected all women from the Netherlands Cancer Registry diagnosed with primary, invasive, stage T12, N01, M0 breast cancer between Jan 1, 2000, and Dec 31, 2004, given either breast-conserving surgery plus radiotherapy or mastectomy, irrespective of axillary staging or dissection or use of adjuvant systemic therapy. Primary outcomes were 10 year overall survival in the entire cohort and breast cancer-specific survival in a representative subcohort of patients diagnosed in 2003 with characteristics similar to the entire cohort. We estimated breast cancer-specific survival by calculating distant metastasis-free and relative survival for every tumour and nodal category. We did multivariable Cox proportional hazard analysis to estimate hazardratios (HRs) for overall and distant metastasis-free survival. We estimated relative survival by calculating excess mortality ratios using life tables of the general population. We did multiple imputation to account for missing data. Findings Of the 37 207 patients included in this study, 21 734 (58%) received breast-conserving surgery plus radiotherapy and 15 473 (42%) received mastectomy. The 2003 representative subcohort consisted of 7552 (20%) patients, of whom 4647 (62%) received breastconserving surgery plus radiotherapy and 2905 (38%) received mastectomy. For both unadjusted and adjusted analysis accounting for various confounding factors, breastconserving surgery plus radiotherapy was significantly associated with improved 10 year overall survival in the whole cohort overall compared with mastectomy (HR 0•51 [95% CI 0•490•53];

The place of public narratives in reproducing social order.

Legal systems work not only to protect individuals and prosecute others in order to maintain `law and order', but they also define the boundaries of what, in a complex and fragmented society, are the agreed social values and symbols which we decide to protect. The complex role of newspaper reporting in these debates forms a part of the public narratives by which law and order are understood. In this article we look at the reporting of the Taylor sisters' trial for murder, for which they were convicted and then, later, released on appeal. The benchmark appeal held that the press coverage of the trial created a real risk of prejudice against the defendants. This example illustrates how mass-circulation newspapers can be seen as agents of conformity, constructing narratives by which it is publicly established what is and is not generally acceptable behaviour surrounding a crime—perhaps at the expense of ensuring effective detection and prosecution of specific criminal behaviour

Newspaper representations of mental illness and the impact of the reporting of 'events' on social policy: The 'framing' of Isabel Schwarz and Jonathan Zito

Concerns have been raised internationally about the role of the media in influencing public opinion and by implication, social policy on mental health issues. In particular, anxieties have been expressed that an 'excessive' focus by the news media on violence in association with mental illness may reinforce pre-existing stereotypes and by escalating public concerns lead to the adoption of policies which place a high priority on the safety of the public. Such assertions are often contained in the numerous studies that record a seemingly disproportionate number of stories featuring violence in association with mental health. What is, however, almost invariably lacking is a developed theory of agency that explains how or why such depictions of mental illness might exert an influence on social policy. This paper critically examines the potential significance of the way in which responsibility for events is constructed for social policy by means of a discourse analysis, inspired by the genealogical work of Michel Foucault. It uses the device of 'frames' originally developed by Goffman to explore the nature of newspaper coverage of two deaths to which causal responsibility for changes in the nature of English social policy in mental health has been attributed. Results presented suggest that attempts to assert a causal influence between media coverage and changes in the nature of social policy must engage with the question of agency