Search

The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers., C12292/A20861 PPRPGM-Nov20\100002

The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09–1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.

Smartphone-based fundus imaging (SBFI) is a low-cost approach for screening of various ophthalmic diseases and particularly suited to resource limited settings. Thus, we assessed how best to upskill alternative healthcare cadres in SBFI and whether quality of obtained images is comparable to ophthalmologists. Ophthalmic assistants and ophthalmologists received a standardized training to SBFI (Heine iC2 combined with an iPhone 6) and 10 training examinations for capturing central retinal images. Examination time, total number of images, image alignment, usable field-of-view, and image quality (sharpness/focus, reflex artifacts, contrast/illumination) were analyzed. Thirty examiners (14 ophthalmic assistants and 16 ophthalmologists) and 14 volunteer test subjects were included. Mean examination time (1st and 10th training, respectively: 2.17 ± 1.54 and 0.56 ± 0.51 min, p

Diabetes is a uniquely quantifiable disease, and as technology and data have proliferated over the past two decades, so have the tools to manage diabetes. Patients and providers have at their disposal devices, applications, and data platforms that generate immense amounts of data, provide critical insights into a patient’s disease, and allow for personalization of treatment plans. However, the proliferation of options also comes with new burdens for providers: selecting the right tool, getting buy-in from leadership, defining the business case, implementation, and maintenance of the new technology. The complexity of these steps can be overwhelming and sometimes lead to inaction, depriving providers and patients of the advantages of technology-assisted diabetes care. Conceptually, the adoption of digital health solutions can be thought of as occurring in five interconnected phases: Needs Assessment, Solution Identification, Integration, Implementation, and Evaluation. There are a number of existing frameworks to help guide much of this process, but relatively little attention has been focused on integration. Integration is a critical phase for a number of contractual, compliance, financial, and technical processes. Missing a step or doing them out of order can lead to significant delays and potentially wasted resources. To address this gap, we have developed a practical, simplified framework for integrating diabetes data and technology solutions that can guide clinicians and clinical leaders on the critical steps in adopting and implementing a new technology.

BACKGROUND: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers. METHODS: 483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)-negative (PRSER-), or ER-positive (PRSER+) breast cancer risk. RESULTS: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions. CONCLUSIONS: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management.

Supplemental material, sj-pdf-1-opp-10.1177_10781552221118841 for Severe acute radiation dermatitis after palbociclib therapy in the setting of palliative radiotherapy by Kristine N Kim, Michael Salerno, Payal D Shah, Jennifer Matro and Michael J LaRiviere in Journal of Oncology Pharmacy Practice

Supplemental material, sj-pdf-1-opp-10.1177_10781552221118841 for Severe acute radiation dermatitis after palbociclib therapy in the setting of palliative radiotherapy by Kristine N Kim, Michael Salerno, Payal D Shah, Jennifer Matro and Michael J LaRiviere in Journal of Oncology Pharmacy Practice

Introduction: Hypoglycemia is the most common acute adverse complication of glucose lowering therapy among patients with diabetes and is associated with poor outcomes, including death. A recent study reported that the rate of hypoglycemia-related hospitalization in the United States increased by 11.7% (from 94 to 105 admissions per 100,000 person years) between 1991 and 2011 and that total annual costs increased to $1.6 billion. Despite these concerns, diabetes care quality established a decade ago has primarily focused on prevention and reducing rates of complications such as hypoglycemia. Although these efforts have been successful and the proportion of patients achieving HbA1c levels below a 7% threshold improved significantly, consequences of these changes may include increased hospital admission rates of hypoglycemia, which now exceed rates of hyperglycemia. Overall, the three studies presented provide an understanding of the risks of hypoglycemia and multifaceted interventions that reduce the rate of hypoglycemia in the hospital setting and U.S. population. Study One: Study one is a literature review of multifaceted interventions that have used an educational component to reduce the rate of hypoglycemia in inpatient settings. The literature search used a combination of search terms, which include ?inpatient hypoglycemia?, ?inpatient low glucose? ?educational prevention?, and ?educational intervention?. Fifteen articles were selected for the review. Three articles focused on the safety and efficacy of insulin order sets, three articles implemented structured insulin order sets and protocols, seven studies focused on computerized insulin order sets and alert systems and two studies focused on root cause analysis and alert systems. The review suggested a need for randomized control trials and interventions that target at-risk populations, interventions that focus on the root causes of hypoglycemia and interventions that use technological enabled education tools (i.e. mobile health). The review also found that education in combination of multifaceted intervention that have used technology have been successful in reducing the rates of hypoglycemia. Study Two: Study two is a pilot randomized control study that examined the risk factors of hypoglycemia and provided a tailored feedback intervention to address those risk factors in the hospital setting. In this RCT study, a convenient sample of diabetes patients (N=85) were recruited in Atlanta. Baseline surveys were conducted to administer survey instrument. Nine months after recruitment, electronic medical reviews were conducted to determine whether the intervention reduced the incidence of hypoglycemia. Univariate and multivariate logistic regression analysis was conducted to determine the predisposing risk factors of hypoglycemia. Logistic regression analysis was also conducted to determine whether the intervention reduced the incidence of hypoglycemia. Results indicated that insulin use and older age (60+) were significant predictors of hypoglycemia occurrence. Results also indicated that the intervention reduced the incidence nine months post recruitment (P=0.046). Ongoing clinician education regarding insulin use and dosing and educational tools and resources targeted for an older population could continue to lower the rate of hypoglycemia occurrence. Study Three: Study three is a cross-sectional analysis of data on 1,642 older adults (ò 65 years) with diabetes from the National Health and Nutrition Examination Survey (NHANES) from 2009 to 2018 who had an HbA1c measurement. The study examined glycemic control levels among older adults with diabetes mellitus by health status and to estimate the potential of overtreatment with hypoglycemia causing medications (insulin or sulfonylureas). A weighted proportion of survey participants with glycemia that was poorly, moderately or tightly controlled across health status categories was conducted. Weighted proportions of participants whose glycemia was tightly controlled and were treated with insulin or sulfonylureas was also conducted. Logistic regression analysis was conducted to assess linear trends in participants with tightly controlled glycemia, their health status and patterns of treatment during the five NHANES surveys. Results indicated that during the 10 years there were no significant changes in proportion with an HbA1c level less than 7% who had complex/intermediate or very complex/poor health (P=0.444). There were significant changes in the proportion with an HbA1c

Columbia Journal of Gender and Law, Vol 39 No 2 (2020): Spring Issue 2020

Aims Changes in the islet vasculature have been implicated in the regulation of beta-cell survival and function during the progression to type 2 diabetes (T2D). Failure of the beta-cell to compensate for the increased insulin demand in obesity eventually leads to diabetes; as a result of the complex interplay of genetic and environmental factors (e.g. ongoing inflammation within the islets) and impaired vascular function. The Angiopoietin/Tie (Ang/Tie) angiogenic system maintains vasculature and is closely related to organ inflammation and angiogenesis. In this study we aimed to identify whether the vessel area within the islets changes in diabetes and whether such changes would be triggered by the Tie-antagonist Ang-2. Methods Immunohistochemical and qPCR analyses to follow islet vascularization and Ang/Tie levels were performed in human pancreatic autopsies and isolated human and mouse islets. The effect of Ang-2 was assessed in beta-cell-specific Ang-2 overexpressing mice during high fat diet (HFD) feeding. Results Islet vessel area was increased in autopsy pancreases from patients with T2D. The vessel markers Tie-1, Tie-2 and CD31 were upregulated in mouse islets upon HFD feeding from 8 to 24 weeks. Ang-2 was transiently upregulated in mouse islets at 8 weeks of HFD and under glucolipotoxic conditions (22.2mMglucose/0.5 mMpalmitate) in vitro in human and mouse islets, in contrast to its downregulation by cytokines (IL-1 beta, IFN-gamma and TNF-alpha). Ang-1 on the other hand was oppositely regulated, with a significant loss under glucolipotoxic condition, a trend to reduce in islets from patients with T2D and an upregulation by cytokines. Modulation of such changes in Ang-2 by its overexpression or the inhibition of its receptor Tie-2 impaired beta-cell function at basal conditions but protected islets from cytokine induced apoptosis. In vivo, beta-cell-specific Ang-2 overexpression in mice induced hypervascularization under normal diet but contrastingly led to hypovascularized islets in response to HFD together with increased apoptosis and reduced beta-cell mass. Conclusions Islet hypervascularization occurs in T2D. A balanced expression of the Ang1/Ang2 system is important for islet physiology. Ang-2 prevents beta-cell mass and islet vascular adaptation in response to HFD feeding with no major influence on glucose homeostasis.

Objective: Ocular ischemic syndrome is a rare blinding condition generally caused by disease of the carotid artery. We describe a 69-year-old female with a 50 pack-year smoking history with aortic arch syndrome causing bilateral ocular ischemic syndrome. Methods: The patient presented with progressive visual loss and temple pain. Slit lamp biomicroscopy revealed bilateral iris neovascularization. This finding prompted a cardiovascular work up. Panretinal photocoagulation with retrobulbar block was performed in the right eye. Results: A temporal artery biopsy was negative. The carotid duplex ultrasound showed only a 1–39% stenosis. MRA revealed a more proximal occlusion of the aortic branch for which she underwent subclavian carotid bypass surgery. At the one month follow up, the right eye suffered profound vision loss secondary to a central retinal artery occlusion. Conclusion: Ocular neovascularization may be one of the clinical manifestations of aortic arch syndrome. This case also illustrates the limitations of relying solely on carotid duplex ultrasound testing. We caution against overly aggressive panretinal photocoagulation utilizing retrobulbar anesthesia., GMS Ophthalmology Cases; 5:Doc14

Objective: Aqueous root extract of Oroxylum indicum was evaluated in rats against dinitrobenzene sulfonic acid (DNBS) induced colitis. Materials and Methods: Rats were pre-treated orally for seven days and continued for four days after the induction of colitis with OIaq (100, 200, and 400 mg/kg) or vehicle. Colitis was induced by intracolonic instillation of 25 mg of DNBS per rat dissolved in 50% alcohol and 4 days later, the colonic mucosal damage was analyzed along with food intake, body weight, colon weight, spleen weight, histological damage, myeloperoxidase (MPO) activity, malondialdehyde (MDA) levels, reduced glutathione (GSH), and nitric oxide levels in colonic tissue homogenate. Results: Significant reduction in gross damage area, weight loss and increase in colonic and spleen weight were evident in test substance-pretreated animals’ dose dependently as compared to vehicle treated control. These effects were confirmed biochemically by a reduction in colonic myeloperoxidase activity, malondialdehyde levels, nitric oxide levels, and increase in reduced glutathione (GSH) levels. Furthermore, microscopic examination revealed diminution of inflammatory cell infiltration and submucosal edema in colon segments of rats treated with OIaq. Conclusion: The results demonstrate the protective effect of OIaq in the animal model of acute colitis possibly through an antioxidant, anti-lipoperoxidative or due to reduction in nitric oxide generation.

Diabetes is a complex metabolic disorder characterized by the failure to maintain normoglycemia stemming from dysfunctional islet of Langerhans. It is caused by an autoimmune destruction of insulin secreting beta-cells in case of type 1 diabetes (T1D), or non-insulin dependent diabetes, caused by lack on insulin action and production in type 2 diabetes (T2D) and by insulin insufficiency during pregnancy as in gestational diabetes mellitus (GDM). T2D accounts for at least 90% of the cases of diabetes, although it may remain undetected or at a pre-diabetic stage for several years. Thus, therapeutic intervention to prevent the progression to T2D is a major goal to subside the incidence of the disease and thus prevent further metabolic complications. T2D is most commonly associated with obesity and thus peripheral insulin resistance. In the face of insulin resistance there occurs an array of molecular mechanisms, one of the major activator being inflammation. In serum, adipose tissue, liver and pancreatic islets from T2D patients, pro-inflammatory cytokines like IL-1beta, CXCL10, TNFalpha, IL-6 have been detected and clinical trials are initiated to prevent inflammatory action. In our study, we showed anti-mouse CXCL10 antibody prevented diabetes progression; it improved glucose tolerance, insulin sensitivity and restored glucose stimulated insulin secretion in the HFD fed mice. CXCL10 antagonism also prevented upregulation of pro-inflammatory cytokines, IL-1beta, IL-6 and CXCL10 mRNA in isolated islets, CXCL10 in adipose tissue and liver of high fat/high sucrose diet (HFD) fed mice. Dipeptidyl peptidase-4 (DPP-4) inhibitors are oral antidiabetics widely in use for T2D treatment. The first agent of its class sitagliptin was approved by the FDA in 2006 and since has been investigated for its direct effects on islet function. The gluco-incretin hormones GIP and GLP-1 secreted by the intestinal endocrine cells potentiate glucose stimulated insulin secretion but are rapidly inactivated by DPP-4. We treated cultured human islets with a diabetic milieu of high glucose, palmitate, cytokines and H2O2 in presence of the DPP-4 inhibitor linagliptin. Linagliptin restored beta-cell function and turnover, via mechanism involving stabilization of secreted GLP-1 in islet supernatants. Obesity induced insulin resistance requires expansion of beta-cell mass to maintain normoglycemia. There occurs a compensatory islet hyperplasia, progressing with altered islet vascularization and possibly angiogenesis, inflammation and eventually leading to reduced beta-cell mass, beta-cell failure and hyperglycemia. The molecular mechanisms involved in the concomitant pathophysiology of islet endothelial cells in T2D has focused on effects mediated by VEGF-A. In this study, we aimed to identify the regulation of and the changes driven by the Angiopoietin/Tie angiogenic factors in islet vascularization and function during the progression of T2D. Ang-1 expressed by perivascular cells and beta-cells and Ang-2 expressed by endothelial cells exert their autocrine and paracrine effects via the cognate receptor Tie-2, on the endothelial cells. Tie-2 signaling maintains quiescent vasculature via constitutive Ang-1 expression whereas Ang-2 is known to be in play in demand for angiogenesis or pathological stimuli involving inflammation. Ang/Tie regulation and thus its role in diabetes and islet vascularization is so far poorly understood. Islet vessel area was increased in autopsy pancreases from T2D subjects, compared to controls. Vessel markers Tie-1, Tie-2 and CD31 were upregulated in mouse islets upon HFD feeding from 8 to 24 weeks. Ang-2 was transiently upregulated in mouse islets at 8 weeks of HFD as well under gluco-lipotoxicity in vitro in human and mouse islets, in contrast to its downregulation with cytokine treatment. Ang-1 on the other hand was oppositely regulated, with reduction under glucolipotoxic conditions and upregulation by cytokine milieu. Modulation of such changes in Ang-2 expression by its overexpression or the inhibition of its receptor Tie-2 impaired beta-cell function at basal conditions but protected islets from cytokine induced apoptosis in vitro. In vivo, beta-cell-specific Ang-2 overexpression in mice induced vascularization under normal diet but contrastingly hypovascularized islets under HFD together with increased apoptosis and reduction of beta-cell mass. Our data show that increased islet hypervascularization is paralleled with T2D. Maintaining physiological Ang-2 levels is important for islet vascularization and beta-cell survival.

May-Thurner syndrome (MTS) has been recognized as a clinical entity for almost six decades. The true incidence rate of MTS is unknown and perhaps ranges from 22 to 32% according to the autopsy studies in the early twentieth century. However, MTS related deep venous thrombosis (DVT) accounts for only 2%-3% of all lower limb DVTS. In MTS, the left common iliac vein is compressed against the fifth lumbar vertebrae by the right common iliac artery, as it crosses in front of the vein. Chronic pulsation of the artery is thought to cause elastin, collagen deposition, and intimal fibrosis leading to formation of venous spur and venous thrombosis. MTS can present as acute or chronic DVT leading to pulmonary embolism (PE), chronic leg pain, chronic ulcers, or skin pigmentation changes. In this case report we have described an interesting case of a 28-year-old Caucasian female who presented for evaluation of shortness of breath (SOB) associated with cough for one week. SOB was found to be secondary to massive bilateral pulmonary embolism resulting from extensive MTS related DVT of the left lower extremity. Patient underwent pharmacomechanical treatment with local thrombolysis, thrombectomy, and venoplasty along with stent placement that extended to inferior vena caval junction. Subsequently patient was discharged on coumadin. MTS should be considered in differentials when faced with a case of unilateral DVT particularly in younger age group.

Background: Prediabetes is a precursor condition to type 2 diabetes mellitus. Previous research and clinical trials have shown that the onset of type 2 diabetes could be delayed or prevented through structured life style modifications such as dietary changes, modest weight loss and moderate-intensity exercise. This study examines U.S adults of different ethnicities that include non-Hispanic white, non-Hispanic black and Mexican Americans and whether their awareness of diabetes risk is associated with their participation in diabetes risk reduction behavior, a combination of physical activity, weight control and fat/calories intake Methods: The 2007-2008 National Health and Nutrition Examination Survey, NHANES, was used to conduct a cross-sectional study of 4083 U.S. adults who were 20 years old and above and were aware of their diabetes risk. The association between the awareness of one’s diabetes risk and the adoption of diabetes risk reduction behavior were examined in present of other risk factors such as age, gender, ethnicity, education, annual family income, BMI, hypertension, mean systolic blood pressure, mean diastolic blood pressure, total cholesterol, LDL, HDL and triglyceride levels. Males and females were examined separately for all analyses performed. Cross tabulation was conducted and p-values were calculated by the Pearson’s chi-square test for the categorical variables which include gender, ethnicity, education, annual family income, adiposity and hypertension. One Way ANOVA and Tukey post hoc tests were conducted for the continuous variables which include age, mean systolic blood pressure, mean diastolic blood pressure, total cholesterol, LDL, HDL and triglyceride levels. Univariate and multivariate analyses were performed to determine the association between the main independent variable, awareness of one’s diabetes risk, and the dependent variable, adoption of diabetes risk reduction behavior, controlling for other risk factors. A p-value of Results: After controlling for age, gender, race, education, annual family income, BMI, hypertension, mean systolic blood pressure, mean diastolic blood pressure, total cholesterol, LDL, HDL, and triglycerides, results from the multivariate analysis showed that subjects who were aware of their diabetes risk were more likely to adopt diabetes risk reduction behavior (OR= 1,734, 95 % CI=1.217-2.470). Females and non-Hispanic blacks, who were aware of their diabetes risk, were also more likely to adopt diabetes risk reduction behavior compared to males, non-Hispanic whites and Mexican Americans. An increase in the levels of education, annual family income and BMI was also associated with the adoption of diabetes risk reduction behavior. Stratification according to gender and ethnicity, showed that Mexican American males and females were more likely to engage in diabetes risk reduction behavior compared to non-Hispanic whites and non-Hispanic blacks (Mexican American males: OR: 2.496, CI: 0.792-7.868; Mexican American females: OR: 2.830, CI: 0.917-8.736). Conclusion: This study provides useful insights for health care providers and public health professionals who are developing health promotion and prevention interventions to address pre diabetes before it develops into type 2 diabetes. This study also allows the development of tailored interventions for specific genders and ethnic groups that are at risk. Results of this study indicate that Mexican Americans and females (in general) are more likely to adopt diabetes risk reduction behavior. Therefore, physicians and health care providers should develop culturally, linguistically and gender- specific education materials and programs for this particular gender and ethnic group. This in turn, may reduce the overall increasing prevalence of diabetes, reduce racial and gender disparities and may have a positive impact on the overall health of the U.S. population.

The dominant paradigm of conservation-reserve planning in economics is to optimize the provision of physical conservation benefits (measured in units like species protected) given a budget constraint. Large-scale biology-based priority setting implies that the value we place on biodiversity and ecosystem function is not affected by human proximity to that natural capital. There is significant evidence, however, that human willingness to pay (WTP) for conservation declines with distance (e.g. Loomis 2000) – a phenomenon we refer to as “spatial value decay”. This paper begins a new strand of the conservation planning literature that takes demand-side factors – the location of people in the landscape and the degree to which their willingness to pay for an environmental amenity depends on proximity to that amenity – into account. We use theoretical models of linear abstract landscapes to explore the impact of demand-side factors on two facets of optimal conservation choices: siting of a single reserve when conservation value is greatest near a critical site in the landscape (optimal targeting), and siting of multiple reserves when fragmentation reduces physical conservation services produced (optimal agglomeration). Our results show how optimal conservation planning might differ from straight ecological prescriptions. While minimum fragmentation is often optimal, planners can usefully employ increased fragmentation to capture value when people’s preferences are not very highly localized. In a targeting problem, the ecologically critical site is often the right thing to protect, but optimal policy balances proximity to critical site with proximity to people. In some scenarios, the payoff to using a reserve design approach that considers demand-side factors is large. Finally, we find that spatial value decay reduces the maximum levels of welfare and environmental services that can be gained from any conservation-planning approach. When spatial value decay is present because people are simply unaware of environmental resources farther away from where they live, education campaigns might serve to increase social welfare and environmental services.

The dominant paradigm of conservation-reserve planning in economics is to optimize the provision of physical conservation benefits (measured in units like species protected) given a budget constraint. Large-scale biology-based priority setting implies that the value we place on biodiversity and ecosystem function is not affected by human proximity to that natural capital. There is significant evidence, however, that human willingness to pay (WTP) for conservation declines with distance (e.g. Loomis 2000) – a phenomenon we refer to as “spatial value decay”. This paper begins a new strand of the conservation planning literature that takes demand-side factors – the location of people in the landscape and the degree to which their willingness to pay for an environmental amenity depends on proximity to that amenity – into account. We use theoretical models of linear abstract landscapes to explore the impact of demand-side factors on two facets of optimal conservation choices: siting of a single reserve when conservation value is greatest near a critical site in the landscape (optimal targeting), and siting of multiple reserves when fragmentation reduces physical conservation services produced (optimal agglomeration). Our results show how optimal conservation planning might differ from straight ecological prescriptions. While minimum fragmentation is often optimal, planners can usefully employ increased fragmentation to capture value when people’s preferences are not very highly localized. In a targeting problem, the ecologically critical site is often the right thing to protect, but optimal policy balances proximity to critical site with proximity to people. In some scenarios, the payoff to using a reserve design approach that considers demand-side factors is large. Finally, we find that spatial value decay reduces the maximum levels of welfare and environmental services that can be gained from any conservation-planning approach. When spatial value decay is present because people are simply unaware of environmental resources farther away from where they live, education campaigns might serve to increase social welfare and environmental services.

In the wake of the tsunami that hit the coastal communities of the Indian Ocean, images of women were splashed over the media’s reports of the catastrophe. But while sympathy for women has garnered a great deal of aid, “[b]eyond the camera lens in the follow-up policies. . .there is a trend for women to be rendered almost invisible.” Reports by women’s groups streaming in from all over the region reflect the same message-women were among the hardest hit by the tsunami, and women continue to be the most marginalized in relief efforts. While the relative lack of women-specific initiatives in the tsunami effort arguably could be attributed to the cultural norms of the region and the particular nature of the disaster there, a broader look at disasters worldwide shows that women’s needs and abilities are systemically ignored in rehabilitation and restoration efforts. Although this trend has been recognized by international organizations ranging from the United Nations (U.N.) General Assembly, the U.N. Population Fund (UNFPA), the Committee for the Elimination of Discrimination Against Women (CEDAW Committee), the U.N. Office for International Strategy for Disaster Reduction (ISDR), the International Labor Organization (ILO), and the European Union (EU), there is yet to be a binding global initiative that explicitly calls for gender-mainstreaming in disaster prevention and reconstruction efforts. As a result, when the time comes for nations to respond quickly and efficiently to disasters, the lessons learned in gender- sensitivity are lost in the tumult once again., Columbia Journal of Gender and Law, Vol. 15 No. 3 (2006)

This study aims to understand the influence of different cultures in the basic purpose and functioning of homes for the old in Norway and India. The study was first conducted at Heimens, (translated as Home) in Norway. The study was later continued in some of the homes for the aged in Bangalore, India. A self-prepared questionnaire was used and the questions were addressed to the Head/ Director and the Nursing staff of the Homes by the author. Conceptual differences in culture were seen in the basic purpose and functioning of the old age homes in India and Norway.

BACKGROUND: BRCA1/2 mutations confer high lifetime risk of breast cancer, although other factors may modify this risk. Whether height or body mass index (BMI) modifies breast cancer risk in BRCA1/2 mutation carriers remains unclear. METHODS: We used Mendelian randomization approaches to evaluate the association of height and BMI on breast cancer risk, using data from the Consortium of Investigators of Modifiers of BRCA1/2 with 14 676 BRCA1 and 7912 BRCA2 mutation carriers, including 11 451 cases of breast cancer. We created a height genetic score using 586 height-associated variants and a BMI genetic score using 93 BMI-associated variants. We examined both observed and genetically determined height and BMI with breast cancer risk using weighted Cox models. All statistical tests were two-sided. RESULTS: Observed height was positively associated with breast cancer risk (HR = 1.09 per 10 cm increase, 95% confidence interval [CI] = 1.0 to 1.17; P = 1.17). Height genetic score was positively associated with breast cancer, although this was not statistically significant (per 10 cm increase in genetically predicted height, HR = 1.04, 95% CI = 0.93 to 1.17; P = .47). Observed BMI was inversely associated with breast cancer risk (per 5 kg/m2 increase, HR = 0.94, 95% CI = 0.90 to 0.98; P = .007). BMI genetic score was also inversely associated with breast cancer risk (per 5 kg/m2 increase in genetically predicted BMI, HR = 0.87, 95% CI = 0.76 to 0.98; P = .02). BMI was primarily associated with premenopausal breast cancer. CONCLUSION: Height is associated with overall breast cancer and BMI is associated with premenopausal breast cancer in BRCA1/2 mutation carriers. Incorporating height and BMI, particularly genetic score, into risk assessment may improve cancer management.

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.

Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3' region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. SIGNIFICANCE: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

BACKGROUND: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers. METHODS: 483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)-negative (PRSER-), or ER-positive (PRSER+) breast cancer risk. RESULTS: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions. CONCLUSIONS: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management.

BACKGROUND: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. METHODS: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. RESULTS: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94-1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85-1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06-1.48) and HR = 1.59 (95% CI: 1.08-2.33) per 5-kg/m2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (Pinteraction < 0.05). CONCLUSION: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.

PURPOSE: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. METHODS: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. RESULTS: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10-72). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10-50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10-22) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10-12) carriers. The associations in the prospective cohort were similar. CONCLUSION: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.

Funder: CIMBA: The CIMBA data management and data analysis were supported by Cancer Research – UK grants C12292/A20861, C12292/A11174. ACA is a Cancer Research -UK Senior Cancer Research Fellow. GCT and ABS are NHMRC Research Fellows. iCOGS: the European Community's Seventh Framework Programme under grant agreement No. 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer (CRN-87521), and the Ministry of Economic Development, Innovation and Export Trade (PSR-SIIRI-701), Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The PERSPECTIVE project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministry of Economy, Science and Innovation through Genome Québec, and The Quebec Breast Cancer Foundation. BCFR: UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the BCFR. BFBOCC: Lithuania (BFBOCC-LT): Research Council of Lithuania grant SEN-18/2015. BIDMC: Breast Cancer Research Foundation. BMBSA: Cancer Association of South Africa (PI Elizabeth J. van Rensburg). CNIO: Spanish Ministry of Health PI16/00440 supported by FEDER funds, the Spanish Ministry of Economy and Competitiveness (MINECO) SAF2014-57680-R and the Spanish Research Network on Rare diseases (CIBERER). COH-CCGCRN: Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under grant number R25CA112486, and RC4CA153828 (PI: J. Weitzel) from the National Cancer Institute and the Office of the Director, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. CONSIT: Associazione Italiana Ricerca sul Cancro (AIRC; IG2014 no.15547) to P. Radice. Italian Association for Cancer Research (AIRC; grant no.16933) to L. Ottini. Associazione Italiana Ricerca sul Cancro (AIRC; IG2015 no.16732) to P. Peterlongo. Jacopo Azzollini is supported by funds from Italian citizens who allocated the 5x1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects ‘5x1000’). DEMOKRITOS: European Union (European Social Fund – ESF) and Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research & Technology: SYN11_10_19 NBCA. Investing in knowledge society through the European Social Fund. DFKZ: German Cancer Research Center. EMBRACE: Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft are supported by Cancer Research UK Grant C5047/A8385. Ros Eeles is also supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. FCCC: The University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program. A.K.G. was funded by R0 1CA140323, R01 CA214545, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship. FPGMX: FISPI05/2275 and Mutua Madrileña Foundation (FMMA). GC-HBOC: German Cancer Aid (grant no 110837, Rita K. Schmutzler) and the European Regional Development Fund and Free State of Saxony, Germany (LIFE - Leipzig Research Centre for Civilization Diseases, project numbers 713-241202, 713-241202, 14505/2470, 14575/2470). GEMO: Ligue Nationale Contre le Cancer; the Association “Le cancer du sein, parlons-en!” Award, the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program and the French National Institute of Cancer (INCa grants 2013-1-BCB-01-ICH-1 and SHS-E-SP 18-015). GEORGETOWN: the Non-Therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI grant P30-CA051008), the Fisher Center for Hereditary Cancer and Clinical Genomics Research, and Swing Fore the Cure. G-FAST: Bruce Poppe is a senior clinical investigator of FWO. Mattias Van Heetvelde obtained funding from IWT. HCSC: Spanish Ministry of Health PI15/00059, PI16/01292, and CB-161200301 CIBERONC from ISCIII (Spain), partially supported by European Regional Development FEDER funds. HEBCS: Helsinki University Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society and the Sigrid Juselius Foundation. HEBON: the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organisation of Scientific Research grant NWO 91109024, the Pink Ribbon grants 110005 and 2014-187.WO76, the BBMRI grant NWO 184.021.007/CP46 and the Transcan grant JTC 2012 Cancer 12-054. HRBCP: Hong Kong Sanatorium and Hospital, Dr Ellen Li Charitable Foundation, The Kerry Group Kuok Foundation, National Institute of Health1R 03CA130065, and North California Cancer Center. HUNBOCS: Hungarian Research Grants KTIA-OTKA CK-80745 and OTKA K-112228. ICO: The authors would like to particularly acknowledge the support of the Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III (organismo adscrito al Ministerio de Economía y Competitividad) and “Fondo Europeo de Desarrollo Regional (FEDER), una manera de hacer Europa” (PI10/01422, PI13/00285, PIE13/00022, PI15/00854, PI16/00563 and CIBERONC) and the Institut Català de la Salut and Autonomous Government of Catalonia (2009SGR290, 2014SGR338 and PERIS Project MedPerCan). IHCC: PBZ_KBN_122/P05/2004. ILUH: Icelandic Association “Walking for Breast Cancer Research” and by the Landspitali University Hospital Research Fund. INHERIT: Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program – grant # CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade – grant # PSR-SIIRI-701. IOVHBOCS: Ministero della Salute and “5x1000” Istituto Oncologico Veneto grant. IPOBCS: Liga Portuguesa Contra o Cancro. kConFab: The National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. MAYO: NIH grants CA116167, CA192393 and CA176785, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201),and a grant from the Breast Cancer Research Foundation. MCGILL: Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade. Marc Tischkowitz is supported by the funded by the European Union Seventh Framework Program (2007Y2013)/European Research Council (Grant No. 310018). MODSQUAD: MH CZ - DRO (MMCI, 00209805), MEYS - NPS I - LO1413 to LF and by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101) to LF, and by Charles University in Prague project UNCE204024 (MZ). MSKCC: the Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, the Andrew Sabin Research Fund and a Cancer Center Support Grant/Core Grant (P30 CA008748). NAROD: 1R01 CA149429-01. NCI: the Intramural Research Program of the US National Cancer Institute, NIH, and by support services contracts NO2-CP-11019-50, N02-CP-21013-63 and N02-CP-65504 with Westat, Inc, Rockville, MD. NICCC: Clalit Health Services in Israel, the Israel Cancer Association and the Breast Cancer Research Foundation (BCRF), NY. NNPIO: the Russian Foundation for Basic Research (grants 17-54-12007, 17-00-00171 and 18-515-12007). NRG Oncology: U10 CA180868, NRG SDMC grant U10 CA180822, NRG Administrative Office and the NRG Tissue Bank (CA 27469), the NRG Statistical and Data Center (CA 37517) and the Intramural Research Program, NCI. OSUCCG: Ohio State University Comprehensive Cancer Center. PBCS: Italian Association of Cancer Research (AIRC) [IG 2013 N.14477] and Tuscany Institute for Tumors (ITT) grant 2014-2015-2016. SEABASS: Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation. SMC: the Israeli Cancer Association. SWE-BRCA: the Swedish Cancer Society. UCHICAGO: NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA125183), R01 CA142996, 1U01CA161032, P20CA233307, American Cancer Society (MRSG-13-063-01-TBG, CRP-10-119-01-CCE), Breast Cancer Research Foundation, Susan G. Komen Foundation (SAC110026), and Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women's Cancer Research Alliance. Mr. Qian was supported by the Alpha Omega Alpha Carolyn L. Cuckein Student Research Fellowship. UCLA: Jonsson Comprehensive Cancer Center Foundation; Breast Cancer Research Foundation. UCSF: UCSF Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center. UKFOCR: Cancer Research UK. UPENN: Breast Cancer Research Foundation; Susan G. Komen Foundation for the cure, Basser Center for BRCA. UPITT/MWH: Hackers for Hope Pittsburgh. VFCTG: Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation. WCP: Dr Karlan is funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124., Background: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. Methods: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. Results: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94–1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85–1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06–1.48) and HR = 1.59 (95% CI: 1.08–2.33) per 5-kg/m2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (Pinteraction < 0.05). Conclusion: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.

Purpose: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. Methods: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)–negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. Results: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25–1.33], P = 3×10−72). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27–1.36], P = 7×10−50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25–1.40], P = 3×10−22) and BRCA2 (HR = 1.44 [95% CI 1.30–1.60], P = 4×10−12) carriers. The associations in the prospective cohort were similar. Conclusion: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.

PURPOSE: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. METHODS: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2. RESULTS: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10-6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. CONCLUSION: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.

Purpose: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. Methods: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)–negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. Results: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25–1.33], P = 3×10−72). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27–1.36], P = 7×10−50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25–1.40], P = 3×10−22) and BRCA2 (HR = 1.44 [95% CI 1.30–1.60], P = 4×10−12) carriers. The associations in the prospective cohort were similar. Conclusion: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.

Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3′ region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25–2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63–5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71–4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12–11.54; P = 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.