Search

Objective Germline BRCA2 pathogenic variants (PVs) are known to cause ~4% of prostate cancer, but other homologous repair genes, BRCA1, ATM, PALB2 and Lynch syndrome genes are also involved. Our objective was to assess the contribution of germline and somatic gene variants to prostate cancer.Methods and analysis We reviewed germline/tumour DNA testing from 450 localised or metastatic prostate cancer cases in NW England mainly from 2022 to 2024. ORs for additional genes used detection rates in controls from the BRIDGES study.Results 450 cases underwent BRCA1/2 germline/somatic testing with 2 germline PVs in BRCA1 (0.4%) and 27 in BRCA2 (6.0%)—total 6.4% and 6/328 (1.8%) in ATM. There were 280 metastatic prostate cancer samples tested with 11 (4%) somatic BRCA2 and 7 (2.7%) somatic ATM identified with 1 somatic BRCA1. Total PVs in BRCA2 were 31/280 (11%), including germline and indeterminate. CDK12 somatic PVs were found in 9/220 (4.1%), including 2 digenic with BRCA2 and 2 which were biallelic.Conclusion In this continuous clinical evaluation, BRCA2 is the most frequently identified prostate cancer gene with over 10% involvement in metastatic disease. BRCA2 and CDK12 somatic PVs do not appear to be mutually exclusive. BRCA1 does not appear to be a significant contributor to prostate cancer progression.

BackgroundBreast cancer is the most common form of cancer in women. Adult weight gain and modifiable health behaviors, including smoking, alcohol intake, and lack of physical activity, are well-known risk factors. Most weight gain in women occurs between the ages of 18 and 35 years. Digital interventions have the potential to address logistical challenges that arise in reaching women in this age range. We designed a digital intervention targeting weight gain prevention and other modifiable health behaviors for young women at increased risk of breast cancer. Women aged 18 to 35 years were recruited to this single-arm intervention study over 2 months to test the acceptability and usability of the intervention, which comprised a group welcome event held via videoconferencing, app, and private Facebook group. ObjectiveThis nested qualitative substudy explored women’s views and experiences of being part of the digital health intervention to inform future intervention development for a feasibility study. MethodsA total of 20 women aged 23 to 35 years who were at increased risk of breast cancer were interviewed via telephone within 1 month after completing the intervention, between February 2023 and March 2023. The women were asked about their experiences of the digital intervention and the extent to which it may have influenced their health behaviors. Data were analyzed thematically and organized using the framework approach. ResultsThe interviews lasted for a median of 37 (IQR 30-46) minutes. Overall, the women perceived the digital health intervention comprising education, tracking, and support to be acceptable for weight gain prevention. In total, 4 themes were generated. A “missed opportunity” in breast cancer prevention services encompasses the lack of services that currently exist for young women at increased risk of breast cancer. The pros and cons of being part of a community encompasses the divergent views that the women had regarding engaging with other women at increased risk. The importance of an interactive app focuses on features that the women would want from the app to promote engagement with the intervention. The different wants and needs of different age groups highlights that an intervention such as this one would need to be customizable to suit the needs of women at different life stages. ConclusionsThere is an unmet need in prevention services for young women aged 18 to 35 years at increased risk of breast cancer. The women perceived the app to be an acceptable intervention for weight gain prevention but emphasized that the intervention would need to be customizable to meet the needs of different age groups within the group of women aged 18 to 35 years. The digital intervention could be a scalable behavior change strategy for UK family history clinics.

Introduction Breast cancer incidence starts to increase exponentially when women reach 30–39 years, hence before they are eligible for breast cancer screening. The introduction of breast cancer risk assessment for this age group could lead to those at higher risk receiving benefits of earlier screening and preventive strategies. Currently, risk assessment is limited to women with a family history of breast cancer only. The Breast CANcer Risk Assessment in Younger women (BCAN-RAY) study is evaluating a comprehensive breast cancer risk assessment strategy for women aged 30–39 years incorporating a questionnaire of breast cancer risk factors, low-dose mammography to assess breast density and polygenic risk. This study will assess the feasibility and acceptability of the BCAN-RAY risk assessment strategy.Methods and analysis This study involves women undergoing risk assessment as part of the BCAN-RAY case-control study (n=750). They will be aged 30–39 years without a strong family history of breast cancer and invited to participate via general practice. A comparison of uptake rates by socioeconomic status and ethnicity between women who participated in the BCAN-RAY study and women who declined participation will be conducted. All participants will be asked to complete self-report questionnaires to assess key potential harms including increased state anxiety (State Trait Anxiety Inventory), cancer worry (Lerman Cancer Worry Scale) and satisfaction with the decision to participate (Decision Regret Scale), alongside potential benefits such as feeling more informed about breast cancer risk. A subsample of approximately 24 women (12 at average risk and 12 at increased risk) will additionally participate in semistructured interviews to understand the acceptability of the risk assessment strategy and identify any changes needed to it to increase uptake.Ethics and dissemination Ethical approval was granted by North West—Greater Manchester West Research Ethics Committee (reference: 22/NW/0268). Study results will be disseminated through peer-reviewed journals, conference presentations and charitable organisations.Trial registration number NCT05305963.

Polygenic Risk Scores (PRS) are a major component of accurate breast cancer risk prediction and have the potential to improve screening and prevention strategies. PRS combine the risk from Single nucleotide polymorphisms (SNPs) associated with breast cancer in Genome Wide Association Studies (GWAS) and explain over 30% of breast cancer heritability. When incorporated into risk models, the more personalised risk assessment derived from PRS, help identify women at higher risk of breast cancer development and enables the implementation of stratified screening and prevention approaches. This review describes the role of PRS in breast cancer risk prediction including the development of PRS and their clinical application. We have also examined the role of PRS within more well-established risk prediction models which incorporate known classic risk factors and discuss the interaction of PRS with these factors and their capacity to predict breast cancer subtypes. Before PRS can be implemented on a population-wide scale, there are several challenges that must be addressed. Perhaps the most pressing of these is the use of PRS in women of non-White European origin, where PRS have been shown to have attenuated risk prediction both in discrimination and calibration. We discuss progress in developing and applying PRS in non-white European populations. PRS represent a significant advance in breast cancer risk prediction and their further development will undoubtedly enhance personalisation.

Abstract Background It is crucial to determine feasibility of risk-stratified screening to facilitate successful implementation. We introduced risk-stratification (BC-Predict) into the NHS Breast Screening Programme (NHSBSP) at three screening sites in north-west England from 2019 to 2021. The present study investigated the views of healthcare professionals (HCPs) on acceptability, barriers, and facilitators of the BC-Predict intervention and on the wider implementation of risk-based screening after BC-Predict was implemented in their screening site. Methods Fourteen semi-structured interviews were conducted with HCPs working across the breast screening pathway at three NHSBSP sites that implemented BC-Predict. Thematic analysis interpreted the data. Results Three pre-decided themes were produced. (1) Acceptability of risk-based screening: risk-stratification was perceived as a beneficial step for both services and women. HCPs across the pathway reported low burden of running the BC-Predict trial on routine tasks, but with some residual concerns; (2) Barriers to implementation: comprised capacity constraints of services including the inadequacy of current IT systems to manage women with different risk profiles and, (3) Facilitators to implementation: included the continuation of stakeholder consultation across the pathway to inform implementation and need for dedicated risk screening admin staff, a push for mammography staff recruitment and guidance for screening services. Telephone helplines, integrating primary care, and supporting access for all language needs was emphasised. Conclusion Risk-stratified breast screening was viewed as a progressive step providing it does not worsen inequalities for women. Implementation of risk-stratified breast screening requires staff to be reassured that there will be systems in place to support implementation and that it will not further burden their workload. Next steps require a comprehensive assessment of the resource needed for risk-stratification versus current resource availability, upgrades to screening IT and building screening infrastructure. The role of primary care needs to be determined. Simplification and clarification of risk-based screening pathways is needed to support HCPs agency and facilitate implementation. Forthcoming evidence from ongoing randomised controlled trials assessing effectiveness of breast cancer risk-stratification will also determine implementation.

Risk-stratified breast cancer screening may improve the balance of screening benefits to harms.We assess a potential new harm: reduced screening attendance in women receiving below average-risk (false reassurance) or higher-risk results (screening avoidance). Following initial screening, 26,668 women in the PROCAS study received breast cancer risk estimates, with attendance recorded for two subsequent screening rounds. First-screen attendance was slightly reduced in below-average (85.6%) but not higher-risk women, compared to other women (86.4%). Second-screen attendance increased for women at higher-risk (89.2%) but not below-average, compared to other women (78.8%). Concerns about this potential harm of risk-stratified screening therefore appear unfounded.

BackgroundBreast cancer is the most common form of cancer in women, and around 20% of cases are associated with factors such as adult weight gain, overweight and obesity, and potentially modifiable health behaviors including high alcohol intake, smoking, lack of physical activity, and breastfeeding. Significant weight gain occurs between the ages of 18 and 35 years; hence, this age group could benefit from weight gain prevention interventions. Population studies have reported that women at increased risk of breast cancer account for a disproportionate amount of cases. Thus, there is a particular need to target weight gain prevention and other health behavior interventions for women at increased risk. A literature review identified no evidence-based apps that cover all relevant health behaviors. With patient and participant involvement from the target population, we have developed a new app to promote healthy behaviors among young women at increased risk of breast cancer. Alongside the app, a Facebook group provides peer support, and a virtual welcome event provides an overview of the project and the opportunity to meet the research team and other study participants. The aim of the intervention is to prevent weight gain via changes to eating habits and physical activity levels, and improve other health behaviors associated with breast cancer. The app includes goal setting and self-monitoring of health behaviors and provides education about breast cancer. ObjectiveThis study aims to assess the acceptability and usability of the app in young women at increased risk of breast cancer, and the feasibility of the study procedures for a future, larger efficacy study. MethodsYoung women (n=35, age 18-35 years) at increased risk of breast cancer (>17% lifetime risk) will be recruited via 2 recruitment procedures: mailed invite from the local breast cancer family history, risk and prevention clinic, and advertisements on social media and websites. Participants will have access to the app and the private Facebook group for 2 months. They will complete questionnaires regarding their health behaviors and breast cancer risk belief at the start and end of the study, complete app rating scales in the middle and at the end of the study, and be invited to give feedback on the app during the study period. Approximately 20 participants will have a semistructured interview at the end of the study regarding their views on the app and trial procedures. ResultsThe trial is ongoing, and the publication of results is anticipated in 2023. ConclusionsThe trial will provide evidence regarding the acceptability and usability of the newly developed app for young women at increased risk of breast cancer. Feedback obtained will be used to improve the app. The trial will also assess the feasibility of the study procedures and how these can be refined for a future efficacy study. Trial RegistrationClinicalTrials.gov NCT05460650; https://clinicaltrials.gov/ct2/show/NCT05460650 International Registered Report Identifier (IRRID)PRR1-10.2196/41246

Abstract Germline TP53 pathogenic variants are rare but associated with a high risk of cancer; they are often identified in the context of clinically diagnosed Li–Fraumeni syndrome predisposing to a range of young onset cancers including sarcomas and breast cancer. The study aim was to conduct a detailed morphological review and immuno‐phenotyping of breast cancer arising in carriers of a germline TP53 pathogenic variant. We compared breast cancers from five defined groups: (1) TP53 carriers with breast cancer (n = 59), (2) early onset HER2‐amplified breast cancer, no germline pathogenic variant in BRCA1/2 or TP53 (n = 55), (3) BRCA1 pathogenic variant carriers (n = 60); (4) BRCA2 pathogenic variant carriers (n = 61) and (5) young onset breast cancer with no known germline pathogenic variant (n = 98). Pathologists assessed a pre‐agreed set of morphological characteristics using light microscopy. Immunohistochemistry (IHC) for HER2, ER, PR, p53, integrin alpha v beta 6 (αvβ6) integrin, α‐smooth muscle actin (α‐SMA) and pSMAD2/3 was performed on tissue microarrays of invasive carcinoma. We confirmed a previously reported high prevalence of HER2‐amplified, ductal no special type invasive breast carcinoma amongst known TP53 germline pathogenic variant carriers 20 of 36 (56%). Furthermore we observed a high frequency of densely sclerotic tumour stroma in cancers from TP53 carriers (29/36, 80.6%) when compared with non‐carriers, 50.9% (28/55), 34.7% (50/144), 41.4% (65/157), 43.8% (95/217) in groups 2–5 respectively. The majority of germline TP53 gene carrier breast tumours had a high intensity of integrin αvβ6, α‐SMA and pSMAD2/3 expression in the majority of cancer cells. In conclusion, aggressive HER2 positive breast cancers with densely sclerotic stroma are common in germline TP53 carriers. High levels of αvβ6 integrin, α‐SMA and pSMAD2/3 expression suggest that the dense stromal phenotype may be driven by upregulated transforming growth factor beta signalling.

Objectives: Proposals to stratify breast screening by breast cancer risk aim to produce a better balance of benefits to harms. Notably, risk estimation calculated from common risk factors and a polygenic risk score would enable high-risk women to benefit from more frequent screening or preventive medication. This service would also identify low-risk women who experience fewer benefits from attending, as lower grade and in situ cancers may be treated unnecessarily. It may therefore be appropriate for low-risk women to attend screening less. This study aimed to elicit views regarding implementing less frequent screening for low-risk women from healthcare professionals who implement risk-stratified screening. Methods: Healthcare professionals involved in the delivery of risk-stratified breast screening were invited to participate in a focus group within the screening setting in which they work or have a telephone interview. Primary care staff were also invited to provide their perspective. Three focus groups and two telephone interviews were conducted with 28 healthcare professionals. To identify patterns across the sample, data were analysed as a single dataset using reflexive thematic analysis. Results: Analysis yielded three themes: Reservations concerning the introduction of less frequent screening , highlighting healthcare professionals’ unease and concerns towards implementing less frequent screening; Considerations for the management of public knowledge , providing views on media impact on public opinion and the potential for a low-risk pathway to cause confusion and raise suspicion regarding implementation motives; and Deliberating service implications and reconfiguration management , where the practicalities of implementation are discussed. Conclusions: Healthcare professionals broadly supported less frequent screening but had concerns about implementation. It will be essential to address concerns regarding risk estimate accuracy, healthcare professional confidence, service infrastructure and public communication prior to introducing less frequent screening for low-risk women.

BackgroundLynch syndrome (LS) predisposes to endometrial cancer (EC), colorectal cancer, and other cancers through inherited pathogenic variants affecting mismatch-repair (MMR) genes. Diagnosing LS in women with EC can reduce subsequent cancer mortality through colonoscopic surveillance and aspirin chemoprevention; it also enables cascade testing of relatives. A growing consensus supports LS screening in EC; however, the expected proportion of test positives, and optimal testing strategy is uncertain. Previous studies from insurance-based healthcare systems were limited by narrow selection criteria, failure to apply reference standard tests consistently, and poor conversion to definitive testing. The aim of this study was to establish the prevalence of LS and the diagnostic accuracy of LS testing strategies in an unselected EC population.Methods and findingsThis was a prospective cross-sectional study carried out at a large United Kingdom gynaecological cancer centre between October 2015 and January 2017. Women diagnosed with EC or atypical hyperplasia (AH) were offered LS testing. Tumours underwent MMR immunohistochemistry (IHC), microsatellite instability (MSI), and targeted MLH1-methylation testing. Women ConclusionsIn this study, we observed that age, family history, and histology are imprecise clinical correlates of LS-EC. IHC outperformed MSI for tumour triage and reliably identified both germline and somatic MMR mutations. The 3.2% proportion of LS-EC is similar to colorectal cancer, supporting unselected screening of EC for LS.

BackgroundLynch syndrome is a hereditary cancer syndrome caused by constitutional pathogenic variants in the DNA mismatch repair (MMR) system, leading to increased risk of colorectal, endometrial and other cancers. The study aimed to identify the incremental costs and consequences of strategies to identify Lynch syndrome in women with endometrial cancer.MethodsA decision-analytic model was developed to evaluate the relative cost-effectiveness of reflex testing strategies for identifying Lynch syndrome in women with endometrial cancer taking the NHS perspective and a lifetime horizon. Model input parameters were sourced from various published sources. Consequences were measured using quality-adjusted life years (QALYs). A cost-effectiveness threshold of £20 000/QALY was used.ResultsReflex testing for Lynch syndrome using MMR immunohistochemistry and MLH1 methylation testing was cost-effective versus no testing, costing £14 200 per QALY gained. There was uncertainty due to parameter imprecision, with an estimated 42% chance this strategy is not cost-effective compared with no testing. Age had a significant impact on cost-effectiveness, with testing not predicted to be cost-effective in patients aged 65 years and over.ConclusionsTesting for Lynch syndrome in younger women with endometrial cancer using MMR immunohistochemistry and MLH1 methylation testing may be cost-effective. Age cut-offs may be controversial and adversely affect implementation.

INTRODUCTION:Increased knowledge of breast cancer risk factors may enable a paradigm shift from one-size-fits-all breast cancer screening to screening and subsequent prevention guided by a woman's individual risk of breast cancer. Professionals will play a key role in informing women about this new personalised screening and prevention programme. Therefore, it is essential to explore professionals' views of the acceptability of this new programme, since this may affect shared decision-making. METHODS:Professionals from three European countries (the Netherlands, United Kingdom, and Sweden) participated in digital concept mapping, a systematic mixed methods approach used to explore complex multidimensional constructs. RESULTS:Across the three countries, professionals prioritised the following five themes which may impact decision-making from the perspective of eligible women: (1) Anxiety/worry; (2) Proactive approach; (3) Reassurance; (4) Lack of knowledge; and (5) Organisation of risk assessment and feedback. Furthermore, Dutch and British professionals expressed concerns regarding the acceptability of a heterogeneous screening policy, suggesting women will question their risk feedback and assigned pathway of care. Swedish professionals emphasised the potential impact of the programme on family relations. CONCLUSIONS:The perspectives of Dutch, British, and Swedish professionals of women's decision-making regarding personalised breast cancer screening and prevention generally appear in line with women's own views of acceptability as previously reported. This will facilitate shared decision-making. However, concerns regarding potential consequences of this new programme for screening outcomes and organisation need to be addressed, since this may affect how professionals communicate the programme to eligible women.

ObjectiveTo develop a generic scale for assessing attitudes towards genetic testing and to psychometrically assess these attitudes in the context of BRCA1/2 among a sample of French general practitioners, breast specialists and gyneco-obstetricians.Study design and settingNested within the questionnaire developed for the European InCRisC (International Cancer Risk Communication Study) project were 14 items assessing expected benefits (8 items) and drawbacks (6 items) of the process of breast/ovarian genetic cancer testing (BRCA1/2). Another item assessed agreement with the statement that, overall, the expected health benefits of BRCA1/2 testing exceeded its drawbacks, thereby justifying its prescription. The questionnaire was mailed to a sample of 1,852 French doctors. Of these, 182 breast specialists, 275 general practitioners and 294 gyneco-obstetricians completed and returned the questionnaire to the research team. Principal Component Analysis, Cronbach's α coefficient, and Pearson's correlation coefficients were used in the statistical analyses of collected data.ResultsThree dimensions emerged from the respondents' responses, and were classified under the headings: "Anxiety, Conflict and Discrimination", "Risk Information", and "Prevention and Surveillance". Cronbach's α coefficient for the 3 dimensions was 0.79, 0.76 and 0.62, respectively, and each dimension exhibited strong correlation with the overall indicator of agreement (criterion validity).ConclusionsThe validation process of the 15 items regarding BRCA1/2 testing revealed satisfactory psychometric properties for the creation of a new scale entitled the Attitudes Towards Genetic Testing for BRCA1/2 (ATGT-BRCA1/2) Scale. Further testing is required to confirm the validity of this tool which could be used generically in other genetic contexts.

Background: In the UK, women are invited for 3-yearly mammography screening, through the NHS Breast Screening Programme (NHSBSP), from the ages of 47–50 years to the ages of 69–73 years. Women with family histories of breast cancer can, from the age of 40 years, obtain enhanced surveillance and, in exceptionally high-risk cases, magnetic resonance imaging. However, no NHSBSP risk assessment is undertaken. Risk prediction models are able to categorise women by risk using known risk factors, although accurate individual risk prediction remains elusive. The identification of mammographic breast density (MD) and common genetic risk variants [single nucleotide polymorphisms (SNPs)] has presaged the improved precision of risk models. Objectives: To (1) identify the best performing model to assess breast cancer risk in family history clinic (FHC) and population settings; (2) use information from MD/SNPs to improve risk prediction; (3) assess the acceptability and feasibility of offering risk assessment in the NHSBSP; and (4) identify the incremental costs and benefits of risk stratified screening in a preliminary cost-effectiveness analysis. Design: Two cohort studies assessing breast cancer incidence. Setting: High-risk FHC and the NHSBSP Greater Manchester, UK. Participants: A total of 10,000 women aged 20–79 years [Family History Risk Study (FH-Risk); UK Clinical Research Network identification number (UKCRN-ID) 8611] and 53,000 women from the NHSBSP [aged 46–73 years; Predicting the Risk of Cancer At Screening (PROCAS) study; UKCRN-ID 8080]. Interventions: Questionnaires collected standard risk information, and mammograms were assessed for breast density by a number of techniques. All FH-Risk and 10,000 PROCAS participants participated in deoxyribonucleic acid (DNA) studies. The risk prediction models Manual method, Tyrer–Cuzick (TC), BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) and Gail were used to assess risk, with modelling based on MD and SNPs. A preliminary model-based cost-effectiveness analysis of risk stratified screening was conducted. Main outcome measures: Breast cancer incidence. Data sources: The NHSBSP; cancer registration. Results: A total of 446 women developed incident breast cancers in FH-Risk in 97,958 years of follow-up. All risk models accurately stratified women into risk categories. TC had better risk precision than Gail, and BOADICEA accurately predicted risk in the 6268 single probands. The Manual model was also accurate in the whole cohort. In PROCAS, TC had better risk precision than Gail [area under the curve (AUC) 0.58 vs. 0.54], identifying 547 prospective breast cancers. The addition of SNPs in the FH-Risk case–control study improved risk precision but was not useful in BRCA1 (breast cancer 1 gene) families. Risk modelling of SNPs in PROCAS showed an incremental improvement from using SNP18 used in PROCAS to SNP67. MD measured by visual assessment score provided better risk stratification than automatic measures, despite wide intra- and inter-reader variability. Using a MD-adjusted TC model in PROCAS improved risk stratification (AUC = 0.6) and identified significantly higher rates (4.7 per 10,000 vs. 1.3 per 10,000; p

Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9 × 10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.

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 association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I(2) = 49.3%; p =

Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ((w)HR) = 1.09 (95% CI 1.02-1.16), p(trend) = 0.017; and n = 3,965, (w)HR = 1.04 (95% CI 0.94-1.16), p(trend) = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM.

Microseminoprotein-beta (MSMB) regulates apoptosis and using genome-wide association studies the rs10993994 single nucleotide polymorphism in the MSMB promoter has been linked to an increased risk of developing prostate cancer. The promoter location of the risk allele, and its ability to reduce promoter activity, suggested that the rs10993994 risk allele could result in lowered MSMB in benign tissue leading to increased prostate cancer risk.MSMB expression in benign and malignant prostate tissue was examined using immunohistochemistry and compared with the rs10993994 genotype. Urinary MSMB concentrations were determined by ELISA and correlated with urinary PSA, the presence or absence of cancer, rs10993994 genotype and age of onset. MSMB levels in prostate tissue and urine were greatly reduced with tumourigenesis. Urinary MSMB was better than urinary PSA at differentiating men with prostate cancer at all Gleason grades. The high risk allele was associated with heterogeneity of MSMB staining and loss of MSMB in both tissue and urine in benign prostate.These data show that some high risk alleles discovered using genome-wide association studies produce phenotypic effects with potential clinical utility. We provide the first link between a low penetrance polymorphism for prostate cancer and a potential test in human tissue and bodily fluids. There is potential to develop tissue and urinary MSMB for a biomarker of prostate cancer risk, diagnosis and disease monitoring.

The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (