Healthy aging delays the neural processing of face features relevant for behavior by 40 ms.

Fast and accurate face processing is critical for everyday social interactions, but it declines and becomes delayed with age, as measured by both neural and behavioral responses. Here, we addressed the critical challenge of understanding how aging changes neural information processing mechanisms to delay behavior. Young (20-36 years) and older (60-86 years) adults performed the basic social interaction task of detecting a face versus noise while we recorded their electroencephalogram (EEG). In each participant, using a new information theoretic framework we reconstructed the features supporting face detection behavior, and also where, when and how EEG activity represents them. We found that occipital-temporal pathway activity dynamically represents the eyes of the face images for behavior ~170 ms poststimulus, with a 40 ms delay in older adults that underlies their 200 ms behavioral deficit of slower reaction times. Our results therefore demonstrate how aging can change neural information processing mechanisms that underlie behavioral slow down.

A case of acute pancreatitis - does step-up protocol always indicated?

Acute pancreatitis (AP) is still one of the most frequent cause of hospitalization. Grading severity of AP due to revised Atlanta classification differentiate: mild, moderately severe and severe AP. Mortality ranges from occasional tomild,8% in moderate, 36%-59% in severe AP. A CASE REPORT: 59-year-old man was hospitalized due to severe acute pancreatitis. Biliary duct obstruction was determined as a reason of AP and intensive treatment was started. The CT scan showed infected post-inflammatory pancreatic cyst. For this reason, endoscopic drainage of the pancreatic cyst to the stomach was performed first and then Jurasz operation. Severe postoperative course required treatment in the Intensive Care Unit (ICU). During the next hospitalization due to the patient's condition deterioration, endoscopic cyst drainage was performed again. Because of ineffectiveness of the performed treatment, the patient was reoperated. Post-operative multi-organ failure, lack of response to the intensive therapy and cachexia because of long-lasting illness, lead into patient's death. CONCLUSIONS: This case demonstrates problem with severe complications of AP which despite of multidisciplinary treatment combining endoscopy, surgery and pharmacology can finally lead to death.

Both PD-1 ligands protect the kidney from ischemia reperfusion injury.

Acute kidney injury (AKI) is a common problem in hospitalized patients that enhances morbidity and mortality and promotes the development of chronic and end-stage renal disease. Ischemia reperfusion injury (IRI) is one of the major causes of AKI and is characterized by uncontrolled renal inflammation and tubular epithelial cell death. Our recent studies demonstrated that regulatory T cells (Tregs) protect the kidney from ischemia reperfusion-induced inflammation and injury. Blockade of programmed death-1 (PD-1) on the surface of Tregs, prior to adoptive transfer, negates their ability to protect against ischemic kidney injury. The present study was designed to investigate the role of the known PD-1 ligands, PD-L1 and PD-L2, in kidney IRI. Administration of PD-L1 or PD-L2 blocking Abs prior to mild or moderate kidney IRI significantly exacerbated the loss of renal function, renal inflammation, and acute tubular necrosis compared with mice receiving isotype control Abs. Interestingly, blockade of both PD-1 ligands resulted in worse injury, dysfunction, and inflammation than did blocking either ligand alone. Genetic deficiency of either PD-1 ligand also exacerbated kidney dysfunction and acute tubular necrosis after subthreshold ischemia. Bone marrow chimeric studies revealed that PD-L1 expressed on non-bone marrow-derived cells is critical for this resistance to IRI. Finally, blockade of either PD-1 ligand negated the protective ability of adoptively transferred Tregs in IRI. These findings suggest that PD-L1 and PD-L2 are nonredundant aspects of the natural protective response to ischemic injury and may be novel therapeutic targets for AKI.

The Deceptively Simple N170 Reflects Network Information Processing Mechanisms Involving Visual Feature Coding and Transfer Across Hemispheres.

A key to understanding visual cognition is to determine "where", "when", and "how" brain responses reflect the processing of the specific visual features that modulate categorization behavior-the "what". The N170 is the earliest Event-Related Potential (ERP) that preferentially responds to faces. Here, we demonstrate that a paradigmatic shift is necessary to interpret the N170 as the product of an information processing network that dynamically codes and transfers face features across hemispheres, rather than as a local stimulus-driven event. Reverse-correlation methods coupled with information-theoretic analyses revealed that visibility of the eyes influences face detection behavior. The N170 initially reflects coding of the behaviorally relevant eye contralateral to the sensor, followed by a causal communication of the other eye from the other hemisphere. These findings demonstrate that the deceptively simple N170 ERP hides a complex network information processing mechanism involving initial coding and subsequent cross-hemispheric transfer of visual features.

Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer.

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.

Fluctuations of visual awareness: combining motion-induced blindness with binocular rivalry.

Binocular rivalry (BR) and motion-induced blindness (MIB) are two phenomena of visual awareness where perception alternates between multiple states despite constant retinal input. Both phenomena have been extensively studied, but the underlying processing remains unclear. It has been suggested that BR and MIB involve the same neural mechanism, but how the two phenomena compete for visual awareness in the same stimulus has not been systematically investigated. Here we introduce BR in a dichoptic stimulus display that can also elicit MIB and examine fluctuations of visual awareness over the course of each trial. Exploiting this paradigm we manipulated stimulus characteristics that are known to influence MIB and BR. In two experiments we found that effects on multistable percepts were incompatible with the idea of a common oscillator. The results suggest instead that local and global stimulus attributes can affect the dynamics of each percept differently. We conclude that the two phenomena of visual awareness share basic temporal characteristics but are most likely influenced by processing at different stages within the visual system.

Autocrine adenosine signaling promotes regulatory T cell-mediated renal protection.

Regulatory T cells (Tregs) suppress the innate inflammation associated with kidney ischemia-reperfusion injury (IRI), but the mechanism is not well understood. Tregs express CD73, the final enzyme involved in the production of extracellular adenosine, and activation of the adenosine 2A receptor (A(2A)R) on immune cells suppresses inflammation and preserves kidney function after IRI. We hypothesized that Treg-generated adenosine is required to block innate immune responses in kidney IRI and that the Treg-generated adenosine would signal through A(2A)Rs on inflammatory cells and, in an autocrine manner, on Tregs themselves. We found that adoptively transferred wild-type Tregs protected wild-type mice from kidney IRI, but the absence of adenosine generation (CD73-deficient Tregs) or adenosine responsiveness (A(2A)R-deficient Tregs) led to inhibition of Treg function. Pharmacologic stimulation of A(2A)R before adoptive transfer augmented the ability of wild-type and CD73-deficient Tregs to suppress kidney IRI. Microarray analysis and flow cytometry revealed that A(2A)R activation enhanced surface PD-1 expression on Tregs in the absence of any other activation signal. Treatment of Tregs with a PD-1 blocking antibody before adoptive transfer reversed their protective effects, even if pretreated with an A(2A)R agonist. Taken together, these results demonstrate that the simultaneous ability to generate and respond to adenosine is required for Tregs to suppress innate immune responses in IRI through a PD-1-dependent mechanism.

Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers.

Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 × 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 × 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 × 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer.

Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers.

INTRODUCTION: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2). METHODS: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework. RESULTS: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 × 10-4). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 × 10-5, P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df-P = 0.007; rs1292011 2df-P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 × 10-5) and there was marginal evidence of association with ER-negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049). CONCLUSIONS: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.

Plasma micronutrients, trace elements, and breast cancer in BRCA1 mutation carriers: an exploratory study.

PURPOSE: Few studies have evaluated the role of micronutrients or trace elements in breast cancer development among BRCA1 mutation carriers. To investigate a possible role of dietary and environmental exposures on cancer risk, we undertook an exploratory study, using a matched case-control design (n = 48 cases and 96 controls), to evaluate the relationships between plasma levels of 14 micronutrients and breast cancer risk among BRCA1 mutation carriers in Poland. METHODS: We estimated the univariate odds ratios (OR) and 95 % confidence intervals (CI) for breast cancer associated with plasma levels for each of 14 micronutrients. RESULTS: Of the 14 analytes quantified, significant differences between cases and controls were seen for two (iron and retinol; p = 0.009 and p = 0.03, respectively). Women in the highest tertile of plasma iron had a 57 % lower risk, compared with those in the lowest quartile (OR = 0.43; 95 % CI 0.18-1.04; p for trend = 0.06). Increasing antimony levels were associated with an increased risk of breast cancer (p for trend = 0.05). Women in the highest tertile had a 2.43-fold increase in breast cancer risk compared with women in the lowest tertile (OR = 2.43; 95 % CI 1.00-5.91). CONCLUSIONS: This study provides some preliminary evidence regarding a role of diet, specifically iron and antimony, in the etiology of BRCA1-associated breast cancer. Prospective studies are necessary to confirm these findings.

Different computations over the same inputs produce selective behavior in algorithmic brain networks.

A key challenge in neuroimaging remains to understand where, when, and now particularly how human brain networks compute over sensory inputs to achieve behavior. To study such dynamic algorithms from mass neural signals, we recorded the magnetoencephalographic (MEG) activity of participants who resolved the classic XOR, OR, and AND functions as overt behavioral tasks (N = 10 participants/task, N-of-1 replications). Each function requires a different computation over the same inputs to produce the task-specific behavioral outputs. In each task, we found that source-localized MEG activity progresses through four computational stages identified within individual participants: (1) initial contralateral representation of each visual input in occipital cortex, (2) a joint linearly combined representation of both inputs in midline occipital cortex and right fusiform gyrus, followed by (3) nonlinear task-dependent input integration in temporal-parietal cortex, and finally (4) behavioral response representation in postcentral gyrus. We demonstrate the specific dynamics of each computation at the level of individual sources. The spatiotemporal patterns of the first two computations are similar across the three tasks; the last two computations are task specific. Our results therefore reveal where, when, and how dynamic network algorithms perform different computations over the same inputs to produce different behaviors.

The CYP17A1 -34T > C polymorphism and breast cancer risk in BRCA1 and BRCA2 mutation carriers.

Exposure to estrogen has a major effect on breast cancer risk. A polymorphism (-34 T > C; rs743572) in the cytochrome P450c17alpha gene (CYP17A1) encoding an enzyme which controls estrogen levels was reportedly associated with breast cancer risk in average risk populations. The effect of this polymorphism on breast or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers has not been thoroughly investigated. With this aim, 2,221 BRCA1 and BRCA2 mutation carriers (1,313 with breast cancer, 279 with ovarian cancer, and 695 asymptomatic carriers), with either BRCA1 (n = 1693) or BRCA2 (n = 528) germline mutations from seven centers were genotyped for the -34 T > C CYP17 polymorphism. Genotyping was accomplished using Taqman allelic discrimination, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) or PCR-based restriction-fragment length polymorphism analysis, and limited sequencing. Data were analyzed using Cox proportional hazards models. The hazard ratios (HRs) for breast cancer was 1.02 (95% CI 0.89-1.17, p = 0.74) and 1.10 (95% CI 0.72-1.67, p = 0.66) for BRCA1 and BRCA2 mutation carriers, respectively. The HRs for ovarian cancer were 1.17 (0.94-1.46, p = 0.17) and 0.91 (0.31-2.67, p = 0.86) for BRCA1 and BRCA2 mutation carriers, respectively. Results remained unaltered when the Israeli cohort (primarily Ashkenazim) was evaluated separately. In conclusion, there was no overall evidence for an association of the -34 T > C CYP17 polymorphism with either breast or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers.

Genetic contribution to all cancers: the first demonstration using the model of breast cancers from Poland stratified by age at diagnosis and tumour pathology.

The aim of the study is to verify the hypothesis that genetic polymorphisms are associated with the predisposition to all malignancies. Using as a model breast cancers from the homogenous Polish population (West Pomeranian region) after stratification of 977 patients by age at diagnosis (under 51 years and above 50 years) and by tumour pathology (ductal cancers--low and high grade, lobular cancers, ER-positive/negative) we tested this hypothesis. Altogether 20 different groups of breast cancer cases have been analyzed. The results were compared to a group of unaffected controls that were matched by age, sex, ethnicity and geographical location and originated from families without cancers of any site among relatives. Molecular alterations selected for analyses included those which have been previously recognized as being associated with breast cancer predisposition. Statistically significant differences between the breast cancer cases and controls were observed in 19 of the 20 analyzed groups. Genetic changes were present in more than 90% of the breast cancer patients in 18 of 20 groups. The highest proportion of cases with constitutional changes-99.3% (139/140) was observed for lobular cancers. The number and type of genetic marker and/or the level of their association with the specific cancer predisposition was different between groups. Markers associated with majority of groups included: BRCA1, CHEK2, p53, TNRnTT, FGFRnAA, XPD CC/AA and XPD GG. Some markers appeared to be group specific and included polymorphisms in CDKN2A, CYP1B1, M3K nAA, and RS67.

With age comes representational wisdom in social signals.

In an increasingly aging society, age has become a foundational dimension of social grouping broadly targeted by advertising and governmental policies. However, perception of old age induces mainly strong negative social biases. To characterize their cognitive and perceptual foundations, we modeled the mental representations of faces associated with three age groups (young age, middle age, and old age), in younger and older participants. We then validated the accuracy of each mental representation of age with independent validators. Using statistical image processing, we identified the features of mental representations that predict perceived age. Here, we show that whereas younger people mentally dichotomize aging into two groups, themselves (younger) and others (older), older participants faithfully represent the features of young age, middle age, and old age, with richer representations of all considered ages. Our results demonstrate that, contrary to popular public belief, older minds depict socially relevant information more accurately than their younger counterparts.

Effect of warm-up intensity on horse-rider dyad's performance in jumping / O efeito da intensidade do aquecimento sobre os resultados de um conjunto cavalo-cavaleiro em competições de saltos

ABSTRACT: The aim of this study was to determine whether there is a correlation between the intensity of warm-up and scores of horse-rider dyads in jumping competitions, and which factors affect the warm-up regime. Three international competitions of 120, 130, and 135cm obstacle height, completed by 82 competitors, were studied. Warm-up intensity was measured by the time spent in the schooling area, number of practice jumping efforts, and coefficient of practice obstacle height. Out of the official final scores in the competitions, penalty points in the round and converted final placings were used as outcome measures. The data were analyzed with Spearman's correlation, multifactorial analysis of variance, and Tukey's test. The rider's sex, part of the world that the riders came from, horse's sex, age, and competitive level (obstacle height) were considered. Results showed that more jumps and higher obstacles during warm-up decrease the horse-rider dyad's performance in jumping competition, whereas the duration of the total warm-up time does not affect the score. Female riders warm up horses longer but jump lower fences than male riders. Riders do not differentiate the warm-up regime with regard to the horse's sex, whereas they considered the horse's age. The warm-up intensity does not increase proportionally to the competitive level.

RESUMO: O objetivo do estudo foi determinar se existe uma correlação entre a intensidade do desempenho de aquecimento e os resultados de um conjunto cavalo-cavaleiro em competições de saltos, assim como também determinar os fatores que afetam esta intensidade. Avaliaram-se três concursos internacionais com obstáculos de 120, 130 e 135cm de altura, que foram completadas por 82 conjuntos. A intensidade do aquecimento foi medida pelo tempo gasto na área de prática, o número de saltos realizados durante o treino e o coeficiente de altura dos obstáculos saltados durante o treino. Dos resultados oficiais finais da competição, utilizaram-se como indicadores os pontos de penalização e o posicionamento obtido. Os dados foram analisados por meio da correlação de Spearman, da análise multivariada de variância e do teste de Tukey. Levaram-se em conta o sexo do cavaleiro, a sua naturalidade; sexo e idade do cavalo e o nível da competição (altura de obstáculos). Os resultados demonstram que quanto mais saltos executados e quanto maiores eram os obstáculos utilizados durante o aquecimento, piores foram os resultados conjunto na competição, contudo, o tempo de aquecimento não afeta os resultados. As amazonas aquecem o cavalo por mais tempo e saltam obstáculos mais baixos do que os homens. Os cavaleiros não diferenciam a intensidade do aquecimento em função do sexo do cavalo, mas, levam em consideração a idade do cavalo. A intensidade do aquecimento não aumenta proporcionalmente com o nível da competição.

How Predictable are "Spontaneous Decisions" and "Hidden Intentions"? Comparing Classification Results Based on Previous Responses with Multivariate Pattern Analysis of fMRI BOLD Signals.

In two replication studies we examined response bias and dependencies in voluntary decisions. We trained a linear classifier to predict "spontaneous decisions" and in the second study "hidden intentions" from responses in preceding trials and achieved comparable prediction accuracies as reported for multivariate pattern classification based on voxel activities in frontopolar cortex. We discuss implications of our findings and suggest ways to improve classification analyses of fMRI BOLD signals that may help to reduce effects of response dependencies between trials.

Multiple fusiform cerebral aneurysms - case report.

BACKGROUND: A true aneurysym is a dilation of arterial lumen as a consequence of congenital or acquired abnormalities leading to a reduction of mechanical resistance of vascular wall, most commonly caused by its defected structure in the form of absence or weakening of the muscular and/or elastic layer. From the pathophysiological point of view, cerebral aneurysms can be classified as 'saccular' - most commonly occurring, and 'other types', including fusiform/dolichoectatic, dissecting, serpentine, posttraumatic, mycotic and giant aneurysms with or without intra-aneurysmal thrombosis. CASE REPORT: We present a rare case of a patient with multiple fusiform dilations of cerebral vessels and giant fusiform aneurysm in supraclinoid segment of the internal carotid artery. The patient presented to hospital because of sudden, severe vertigo with nausea, impaired balance and disturbed vision. Vascular anomalies were detected on CT scanning without contrast. The diagnostic work-up was complemented by CT angiography, MRI and cerebral angiography. CONCLUSIONS: Aneurysm located within the intracranial arteries is one of the most common vascular defects of the brain. The number, size and location of aneurysms are highly variable. Aneurysms can have either supra- or infratentorial location, affecting a single or multiple arteries within one or both brain hemispheres. There is often a correlation between the location of the aneurysm and its etiology, as in case of so-called mirror-image aneurysms. Symmetrically located aneurysms may indicate a defect in vascular structure. Asymmetric location, as in the patient described above, is more likely due to acquired causes, mainly atherosclerosis, but also septic emboli or blood disorders.

Dendritic cells tolerized with adenosine A2AR agonist attenuate acute kidney injury.

DC-mediated NKT cell activation is critical in initiating the immune response following kidney ischemia/reperfusion injury (IRI), which mimics human acute kidney injury (AKI). Adenosine is an important antiinflammatory molecule in tissue inflammation, and adenosine 2A receptor (A2AR) agonists protect kidneys from IRI through their actions on leukocytes. In this study, we showed that mice with A2AR-deficient DCs are more susceptible to kidney IRI and are not protected from injury by A2AR agonists. In addition, administration of DCs treated ex vivo with an A2AR agonist protected the kidneys of WT mice from IRI by suppressing NKT production of IFN-γ and by regulating DC costimulatory molecules that are important for NKT cell activation. A2AR agonists had no effect on DC antigen presentation or on Tregs. We conclude that ex vivo A2AR-induced tolerized DCs suppress NKT cell activation in vivo and provide a unique and potent cell-based strategy to attenuate organ IRI.

A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers.

BACKGROUND: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers. METHODS: IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers. RESULTS: Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 (HR, 1.43; 95% confidence interval (CI), 1.06-1.92; P = 0.019) and BRCA2 mutation carriers (HR, 2.21; 95% CI, 1.39-3.52, P = 0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class II mutations than class I mutations (class II HR, 1.86; 95% CI, 1.28-2.70; class I HR, 0.86; 95%CI, 0.69-1.09; P(difference), 0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR, 2.42; P = 0.03). CONCLUSION: The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class II mutation carriers. IMPACT: These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers.

Common variants at the 19p13.1 and ZNF365 loci are associated with ER subtypes of breast cancer and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.

BACKGROUND: Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). METHODS: Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined. RESULTS: We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07-1.27; P = 7.42 × 10(-4)] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73-0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94-1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05-1.29; P = 3.8 × 10(-4)) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10-1.52; P = 1.8 × 10(-3)). CONCLUSIONS: 19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers. IMPACT: These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers.