Corynoxine promotes TFEB/TFE3-mediated autophagy and alleviates Aß pathology in Alzheimer's disease models.

Autophagy impairment is a key factor in Alzheimer's disease (AD) pathogenesis. TFEB (transcription factor EB) and TFE3 (transcription factor binding to IGHM enhancer 3) are nuclear transcription factors that regulate autophagy and lysosomal biogenesis. We previously showed that corynoxine (Cory), a Chinese medicine compound, protects neurons from Parkinson's disease (PD) by activating autophagy. In this study, we investigated the effect of Cory on AD models in vivo and in vitro. We found that Cory improved learning and memory function, increased neuronal autophagy and lysosomal biogenesis, and reduced pathogenic APP-CTFs levels in 5xFAD mice model. Cory activated TFEB/TFE3 by inhibiting AKT/mTOR signaling and stimulating lysosomal calcium release via transient receptor potential mucolipin 1 (TRPML1). Moreover, we demonstrated that TFEB/TFE3 knockdown abolished Cory-induced APP-CTFs degradation in N2aSwedAPP cells. Our findings suggest that Cory promotes TFEB/TFE3-mediated autophagy and alleviates Aß pathology in AD models.

Suicide risk profiles among service members and veterans exposed to suicide.

OBJECTIVES: Rates of suicide exposure are high among service members and Veterans and are especially concerning given the link between suicide exposure and subsequent suicide risk. However, to date, it is unclear which individuals who are exposed to suicide are subsequently at high risk for suicide. Latent profile analysis (LPA) can provide information on unique risk profiles and subgroups of service members and Veterans who have higher suicide risk after suicide exposure, which has not yet been empirically studied. The purpose of this study was to utilize LPA to identify subgroups of service members and Veterans who are at the highest risk for suicidal thoughts and behaviors following suicide exposure. METHODS: We analyzed data using LPA from 2570 service members and Veterans (82.1% male, 69.5% White, and 12.1% Latino/a/x) who completed the Military Suicide Research Consortium's Common Data Elements, a battery of self-report suicide-related measures. Psychopathology, substance use, mental health service utilization, interpersonal theory of suicide, and suicide exposure variables were used to validate classes. RESULTS: Three latent classes emerged from analyses, one low-risk class and two-high risk classes with differing profile compositions (one primarily differentiated by anxiety symptoms and one differentiated by substance use). CONCLUSION: Class-specific recommendations for suicide prevention efforts will be discussed.

Associations of vulnerability to stressful life events with suicide attempts after active duty among high-risk soldiers: results from the Study to Assess Risk and Resilience in Servicemembers-longitudinal study (STARRS-LS).

BACKGROUND: The transition from military service to civilian life is a high-risk period for suicide attempts (SAs). Although stressful life events (SLEs) faced by transitioning soldiers are thought to be implicated, systematic prospective evidence is lacking. METHODS: Participants in the Army Study to Assess Risk and Resilience in Servicemembers (STARRS) completed baseline self-report surveys while on active duty in 2011-2014. Two self-report follow-up Longitudinal Surveys (LS1: 2016-2018; LS2: 2018-2019) were subsequently administered to probability subsamples of these baseline respondents. As detailed in a previous report, a SA risk index based on survey, administrative, and geospatial data collected before separation/deactivation identified 15% of the LS respondents who had separated/deactivated as being high-risk for self-reported post-separation/deactivation SAs. The current report presents an investigation of the extent to which self-reported SLEs occurring in the 12 months before each LS survey might have mediated/modified the association between this SA risk index and post-separation/deactivation SAs. RESULTS: The 15% of respondents identified as high-risk had a significantly elevated prevalence of some post-separation/deactivation SLEs. In addition, the associations of some SLEs with SAs were significantly stronger among predicted high-risk than lower-risk respondents. Demographic rate decomposition showed that 59.5% (s.e. = 10.2) of the overall association between the predicted high-risk index and subsequent SAs was linked to these SLEs. CONCLUSIONS: It might be possible to prevent a substantial proportion of post-separation/deactivation SAs by providing high-risk soldiers with targeted preventive interventions for exposure/vulnerability to commonly occurring SLEs.

Predicting suicide attempts among U.S. Army soldiers after leaving active duty using information available before leaving active duty: results from the Study to Assess Risk and Resilience in Servicemembers-Longitudinal Study (STARRS-LS).

Suicide risk is elevated among military service members who recently transitioned to civilian life. Identifying high-risk service members before this transition could facilitate provision of targeted preventive interventions. We investigated the feasibility of doing this by attempting to develop a prediction model for self-reported suicide attempts (SAs) after leaving or being released from active duty in the Study to Assess Risk and Resilience in Servicemembers-Longitudinal Study (STARRS-LS). This study included two self-report panel surveys (LS1: 2016-2018, LS2: 2018-2019) administered to respondents who previously participated while on active duty in one of three Army STARRS 2011-2014 baseline self-report surveys. We focus on respondents who left active duty >12 months before their LS survey (n = 8899). An ensemble machine learning model using predictors available prior to leaving active duty was developed in a 70% training sample and validated in a 30% test sample. The 12-month self-reported SA prevalence (SE) was 1.0% (0.1). Test sample AUC (SE) was 0.74 (0.06). The 15% of respondents with highest predicted risk included nearly two-thirds of 12-month SAs and over 80% of medically serious 12-month SAs. These results show that it is possible to identify soldiers at high post-transition self-report SA risk before the transition. Future model development is needed to examine prediction of SAs assessed by administrative data and using surveys administered closer to the time of leaving active duty.

Routinized categorization of suicide risk into actionable strata: Establishing the validity of an existing suicide risk assessment framework in an outpatient sample.

OBJECTIVE: The Suicide Risk Assessment and Management Decision Tree (DT) is a clinician-administered assessment that leads to risk categorizations that correspond with actionable strata. This study investigated the construct validity and test-retest reliability of the DT risk categories across two time points. METHOD: Outpatients (N = 731) completed a battery of self-report measures. Spearman's correlations were used to examine the relationships between DT suicide risk level and suicidal symptoms, theory-based risk factors, psychiatric correlates, and DT suicide risk level at Timepoint 2. Correlations were analyzed for significant differences to examine the divergent validity of the DT. RESULTS: Results, overall, were in line with hypotheses, with the exception of depression and thwarted belongingness. CONCLUSIONS: Findings provide evidence for the reliability, convergent validity, and discriminant validity of the DT. This clinician-administered suicide risk assessment may be useful for standardization of the assessment and management of suicide risk in outpatient clinical settings.

The necessity, validity, and clinical utility of a new diagnostic entity: Acute suicidal affective disturbance.

OBJECTIVE: Here we argue for the necessity, validity, and clinical utility of a new diagnostic entity, acute suicidal affective disturbance (ASAD). METHOD: We expand on the conceptual, clinical, and practical rationale for ASAD, propose its defining features, describe research results to date, and suggest avenues for future research. RESULTS: There is accruing evidence for the existence of a previously unclassified, rapid-onset mood disturbance that geometrically escalates and regularly results in life-threatening behavior. CONCLUSIONS: ASAD research may not only improve the field's understanding of suicidal behavior but also enhance clinical effectiveness and save lives.

Do Undiagnosed Suicide Decedents Have Symptoms of a Mental Disorder?

BACKGROUND: Psychological autopsy studies consistently report that the rate of detected mental disorders among suicide decedents is below 100%. This implies three possibilities: (a) a subset of suicide decedents did not have a mental disorder at the time of death; (b) all suicide decedents suffered from a mental disorder, but some were undetected due to methodological limitations; and/or (c) suicide decedents with an undetected mental disorder displayed significant and perhaps subclinical features of a mental disorder. OBJECTIVE: In this article, we examined these possibilities by evaluating the differences in symptoms and stressors between suicide decedents who were undiagnosed and those diagnosed with a mental disorder at the time of death. METHOD: We reviewed 130 case studies of community-based suicide decedents originally described in Robins' (1981) psychological autopsy study. RESULTS: Without exception, suicide decedents in Robins' sample suffered either from a clearly diagnosable mental disorder or displayed features indicative of a significant, even if subclinical, presentation of a mental disorder. Undiagnosed and diagnosed suicide decedents did not significantly differ with regards to demographics, violence of suicide method, suicide attempt history, the number and intensity of stressful life events preceding death, and whether their death was a murder-suicide. CONCLUSION: Although clearly not all who suffer from mental disorders will die by suicide, these findings imply that all who die by suicide appear to exhibit, at minimum, subclinical psychiatric symptoms with the great majority showing prominent clinical symptoms. We conclude with clinical implications and recommendations for future study.

Does the timing of suicide risk assessments influence ratings of risk severity?

Clinicians are often tasked with identifying and managing patients who are at risk for suicide. Therefore, greater understanding of factors that impact the efficacy of suicide risk assessments (SRA) are of critical importance. One potential factor that may affect assessments of risk severity is the timing of the evaluation during clinical interview. Given that some patients are reluctant to disclose suicide-related symptoms, it is possible that asking about suicide at the beginning of an interview elicits more false negatives. It is also possible that if risk assessments are conducted in a manner that is encouraging to the patient, timing does not significantly impact patient report. This study examined whether SRA timing within an initial intake interview affects risk severity ratings. Adult psychiatric outpatients (N=169) were randomly assigned to receive a SRA during the beginning or middle of a one-hour intake. We failed to find a significant difference in suicide risk ratings between those who were evaluated at the beginning as compared to the middle of intake (14% versus 15% rated at elevated risk). Findings were not moderated by age, gender, or attempt history. Our results provide preliminary evidence that the timing of SRA may not impact risk severity ratings.

Characterizing Positive and Negative Emotional Experiences in Young Adults With Borderline Personality Disorder Symptoms.

OBJECTIVES: Some researchers suggest that borderline personality disorder (BPD) is characterized by elevated negative emotion; others argue that BPD involves both reduced positive and increased negative emotion. This study characterizes the emotional experiences of individuals with BPD symptoms in a combined university and community sample. METHOD: Participants (N = 150) completed a clinical interview assessing BPD symptoms and self-report measures of positive and negative emotion. A subset (n = 106) completed a measure of emotion daily for 2 weeks. Pearson's correlations and multilevel modeling were used to examine the cross-sectional and longitudinal relationships between BPD symptoms and emotions. RESULTS: BPD symptoms were robustly related to increased negative emotion; this relationship remained after accounting for positive emotion. BPD symptoms were weakly related to decreased positive emotion; this relationship was no longer significant after accounting for negative emotion. BPD symptoms predicted higher levels of negative and not positive emotion over 14 days. These patterns held for subscales assessing intensity, frequency, and duration of negative and positive emotions. CONCLUSION: Findings suggest that individuals with BPD features are chiefly distinguished by elevated negative emotional experience.

Improved Clinical Functioning for Patients Receiving Fee Discounts That Reward Treatment Engagement.

OBJECTIVE: Financial incentives may have utility in promoting psychotherapy attendance and adherence, leading to improved clinical functioning. This study presents results from a novel application of financial incentives-a progressively lowered pay scale that rewards therapy attendance and adherence. METHOD: Overall, 110 outpatients participated; 56 patients (51%) were enrolled in the financial incentives condition and received a 5% fee discount-applied iteratively across sessions-if they followed defined criteria (e.g., completed homework). RESULTS: There were no statistically significant differences between groups in terms of the number of sessions attended, therapy duration, and number of no-shows and cancellations. However, adjusting for Global Assessment of Functioning (GAF) at intake, patients receiving the financial incentives had significantly higher GAF rating at termination compared with those who did not receive the intervention. CONCLUSIONS: Financial incentives that reward therapy attendance and adherence with discounted fees is associated with improved clinical functioning.

Eating Disorder Symptoms and Suicidal Ideation: The Moderating Role of Disgust.

Disgust has been implicated as a factor that maintains and exacerbates eating disorder (ED) symptoms. Emerging research suggests that disgust may be a risk factor for suicidality. Given the high rates of suicidality among individuals with EDs, we propose that disgust may contribute to the link between EDs and suicidality. To test this hypothesis, self-report data were collected from 341 young adults (66% women). Cross-sectional associations between disgust with the self, others and the world and disgust sensitivity and propensity, ED symptoms and suicidal ideation were examined using multivariate regression analyses. ED symptoms and body dissatisfaction were associated with increased suicidal ideation at high levels of disgust with the self and the world; at low levels of disgust, ED symptoms and body dissatisfaction did not significantly relate to suicidal ideation. Disgust may indicate risk for suicidal ideation among individuals with eating psychopathology.

Routinized Assessment of Suicide Risk in Clinical Practice: An Empirically Informed Update.

OBJECTIVE: Empirically informed suicide risk assessment frameworks are useful in guiding the evaluation and treatment of individuals presenting with suicidal symptoms. Joiner et al. (1999) formulated one such framework, which has provided a concise heuristic for the assessment of suicide risk. The purpose of this review is to ensure compatibility of this suicide risk assessment framework with the growing literature on suicide-related behaviors. METHODS: This review integrates recent literature on suicide risk factors and clinical applications into the existing model. Further, we present a review of risk factors not previously included in the Joiner et al. (1999) framework, such as the interpersonal theory of suicide variables of perceived burdensomeness, thwarted belongingness, and capability for suicide (Joiner, 2005; Van Orden et al., 2010) and acute symptoms of suicidality (i.e., agitation, irritability, weight loss, sleep disturbances, severe affective states, and social withdrawal). RESULTS: These additional indicators of suicide risk further facilitate the classification of patients into standardized categories of suicide risk severity and the critical clinical decision making needed for the management of such risk. CONCLUSIONS: To increase the accessibility of empirically informed risk assessment protocols for suicide prevention and treatment, an updated suicide risk assessment form and decision tree are provided.

Dangerous Words? An Experimental Investigation of the Impact of Detailed Reporting About Suicide on Subsequent Risk.

OBJECTIVE: Media reporting guidelines exist for suicide-related content; however, no experimental studies have examined the impact of guideline violations. As such, we utilized an experimental design to determine whether reading an article about suicide that violated guidelines would impact mood and suicidality relative to the same article without violations and to an article detailing death by cancer, both immediately and during 1-month follow-up. METHOD: 273 students were randomly assigned to read one of three articles (1) an article that violated suicide reporting guidelines, (2) the same article with violations removed, or (3) an article that details death by cancer. RESULTS: Individuals assigned to read the original suicide article were no more upset immediately afterwards or during 1-month follow-up. Amongst participants with prior ideation, those who read the original article reported a lower likelihood of future attempt relative to either other condition. CONCLUSION: Results indicate some reporting guidelines may be unnecessary. Amongst individuals at risk for suicide, some guideline violations may be associated with a decreased likelihood of future attempt and result in a decrease in negative affect. Clinically, these results highlight the potential utility of exposing clients to in depth educational materials about suicide while mitigating concerns regarding certain aspects of the content.

Evaluating resilience in response to COVID-19 pandemic stressors among veteran mental health outpatients.

There is a public health need to understand mental health vulnerabilities to COVID-19 pandemic-related stressors and promote resilience among high-risk populations with preexisting psychiatric conditions. Recent cross-sectional studies suggest increases in mental health distress (e.g., depression and anxiety) during the pandemic. The present study expands upon these emerging findings using longitudinal latent modeling and hierarchical linear regressions. Consistent with the developmental psychopathology literature on resilience, we distinguished between promotive or risk (i.e., main effect), and protective or vulnerability (i.e., moderation) effects on mental health during the pandemic. At a large medical center, 398 veterans receiving outpatient mental health care provided prepandemic (Time 1) and during pandemic (Time 2) assessments of mental and physical health-related distress. Additional Time 2 questionnaires assessed pandemic-related stressors and positive behavioral adaptations in the summer of 2020. As expected, total stressor scores predicted longitudinal worsening of self-reported mental (ß = -.205) and physical health (ß = -.217). Positive behavioral adaptations enacted during the pandemic moderated and protected against stressor effects on mental health (ß = .160). In addition, the presence of substance use disorders moderated and conferred vulnerability to stressor effects on physical health (ß = -.158). Thus, higher COVID-19 pandemic stressor exposure may have exacerbated mental and physical health distress among veterans with common forms of psychopathology. Nevertheless, behavioral activation, purposeful maintenance of social connections, and focused treatment for substance misuse may be important intervention targets for reducing the longitudinal impact of pandemic stressors and enhancing resilience among people with mental illness. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Prospective Associations of Military Discharge Characterization with Post-active Duty Suicide Attempts and Homelessness: Results from the Study to Assess Risk and Resilience in Servicemembers-Longitudinal Study (STARRS-LS).

INTRODUCTION: Active duty service members transitioning to civilian life can experience significant readjustment stressors. Over the past two decades of the United States' longest sustained conflict, reducing transitioning veterans' suicidal behavior and homelessness became national priorities. However, it remains a significant challenge to identify which service members are at greatest risk of these post-active duty outcomes. Discharge characterization, which indicates the quality of an individual's military service and affects eligibility for benefits and services at the Department of Veterans Affairs, is a potentially important indicator of risk. MATERIALS AND METHODS: This study used data from two self-report panel surveys of the Study to Assess Risk and Resilience in Servicemembers-Longitudinal Study (STARRS-LS) (LS1: 2016-2018, n = 14,508; and LS2: 2018-2019, n = 12,156), which were administered to respondents who previously participated while on active duty in one of the three Army STARRS baseline self-report surveys (2011-2014): the New Soldier Study (NSS), a survey of soldiers entering basic training; All Army Study, a survey of active duty soldiers around the world; and the Pre-Post Deployment Study, a survey of soldiers before and after combat deployment. Human Subjects Committees of the participating institutions approved all recruitment, informed consent, and data collection protocols. We used modified Poisson regression models to prospectively examine the association of discharge characterization (honorable, general, "bad paper" [other than honorable, bad conduct, dishonorable], and uncharacterized [due to separation within the first 180 days of service]) with suicide attempt (subsample of n = 4334 observations) and homelessness (subsample of n = 6837 observations) among those no longer on active duty (i.e., separated or deactivated). Analyses controlled for other suicide attempt and homelessness risk factors using standardized risk indices that were previously developed using the LS survey data. RESULTS: Twelve-month prevalence rates of self-reported suicide attempts and homelessness in the total pooled LS sample were 1.0% and 2.9%, respectively. While not associated with suicide attempt risk, discharge characterization was associated with homelessness after controlling for other risk factors. Compared to soldiers with an honorable discharge, those with a bad paper discharge had an increased risk of homelessness in the total sample (relative risk [RR] = 4.4 [95% CI = 2.3-8.4]), as well as within subsamples defined by which baseline survey respondents completed (NSS vs. All Army Study/Pre-Post Deployment Study), whether respondents had been separated (vs. deactivated), and how much time had elapsed since respondents were last on active duty. CONCLUSIONS: There is a robust association between receiving a bad paper discharge and post-separation/deactivation homelessness. Policies that enhance transition assistance and access to mental healthcare for high-risk soldiers may aid in reducing post-separation/deactivation homelessness among those who do not receive an honorable discharge.

Exploring the link between MORF4L1 and risk of breast cancer.

INTRODUCTION: Proteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens. METHODS: Protein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk. RESULTS: A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to γ-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells. However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, Ptrend = 0.45 and 0.05, P2df = 0.51 and 0.14, respectively; and rs10519219, Ptrend = 0.92 and 0.72, P2df = 0.76 and 0.07, respectively. CONCLUSIONS: While the present study expands on the role of MRG15 in the control of genomic stability, weak associations cannot be ruled out for potential low-penetrance variants at MORF4L1 and BrCa risk among BRCA2 mutation carriers.

Prevalence and correlates of past-month suicidal thoughts, suicide attempts, and non-suicidal self-injury among adults in a partial hospital program.

OBJECTIVE: This study examined the prevalence and cross-sectional correlates of past-month suicidal thoughts, suicide attempts, interrupted attempts, aborted attempts, and non-suicidal self-injury (NSSI) among patients seeking treatment at a partial hospitalization program (PHP). METHOD: 1063 patients (54% female, 87% white, mean age = 33.6 years) receiving treatment at a PHP completed self-report questionnaires and the Columbia-Suicide Severity Rating Scale as part of routine clinical monitoring upon admission to the program. We examined demographic and clinical cross-sectional correlates of self-injurious thoughts and behaviors (SITBs) using descriptive statistics, ordinal regression, and logistic regression analyses. RESULTS: In the past month, 44.6% of patients reported active suicidal thoughts, 5.6% reported a suicide attempt, 1.8% reported an interrupted attempt, 5.5% reported an aborted attempt, and 16.6% reported NSSI. Inpatient referral source (ORs = 2.45-5.28), minority sexual orientation (ORs = 1.43-6.94), and more Borderline Personality Disorder (BPD) symptoms (ORs = 1.09-1.23) were each associated with at least three of the five SITBs examined. CONCLUSIONS: This study highlights elevated rates of suicidal thoughts, suicide attempts, and NSSI in a partial hospital sample. Given that past attempts predict future attempts and death by suicide, support during the transition from inpatient to outpatient care via programs such as PHPs is needed. Patients referred from inpatient treatment, who identity as a sexual minority, and with more BPD symptoms may require additional support and safety monitoring. Further work is indicated to better understand how PHP patients' SITBs change during and after partial hospitalization.

User Engagement and Usability of Suicide Prevention Apps: Systematic Search in App Stores and Content Analysis.

BACKGROUND: People with suicidal thoughts are more inclined to seek technology-delivered interventions than in-person forms of treatment, making mobile apps for suicide prevention an ideal platform for treatment delivery. This review examines apps designed for suicide prevention, with a specific focus on user engagement. OBJECTIVE: This study aims to update the literature and broadly evaluate the landscape of mobile health apps for suicide prevention; examine apps with key features and primary approaches to suicide prevention; and systematically evaluate the engagement, functionality, aesthetics, and information of the apps. METHODS: All apps related to suicidal thoughts and behaviors were identified in the Google Play and iOS app stores and were systematically reviewed for their content and quality. The mobile app rating scale (MARS) was used to evaluate app usability and engagement. RESULTS: Of the 66 apps identified, 42 (64%) were specifically designed for people with suicidal ideation, and 59 (89%) had at least one best practice feature for suicide risk reduction. The mean overall MARS score of all apps was 3.5 (range 2.1-4.5), with 83% (55/66) of apps having a minimum acceptability score of 3. The total MARS score was not associated with the user app rating (r=-0.001; P=.99) or the number of features (r=0.24; P=.09). CONCLUSIONS: This study identified many usable and engaging apps in app stores designed for suicide prevention. However, there are only limited apps for clinicians. Thus, mobile apps for suicide prevention should be carefully developed and clinically evaluated.

Genetic diagnosis of familial breast cancer using clonal sequencing.

Using conventional Sanger sequencing as a reference standard, we compared the sensitivity, specificity, and capacity of the Illumina GA II platform for the detection of TP53, BRCA1, and BRCA2 mutations in established tumor cell lines and DNA from patients with germline mutations. A total of 656 coding variants were identified in four cell lines and 65 patient DNAs. All of the known pathogenic mutations (including point mutations and insertions/deletions of up to 16 nucleotides) were identified, using a combination of the Illumina data analysis pipeline with custom and commercial sequence alignment software. In our configuration, clonal sequencing outperforms current diagnostic methods, providing a reduction in analysis times and in reagent costs compared with conventional sequencing. These improvements open the possibility of BRCA1/2 testing for a wider spectrum of at-risk women, and will allow the genetic classification of tumors prior to the use of novel PARP inhibitors to treat BRCA-deficient breast cancers.

Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers.

INTRODUCTION: Current attempts to identify genetic modifiers of BRCA1 and BRCA2 associated risk have focused on a candidate gene approach, based on knowledge of gene functions, or the development of large genome-wide association studies. In this study, we evaluated 24 SNPs tagged to 14 candidate genes derived through a novel approach that analysed gene expression differences to prioritise candidate modifier genes for association studies. METHODS: We successfully genotyped 24 SNPs in a cohort of up to 4,724 BRCA1 and 2,693 BRCA2 female mutation carriers from 15 study groups and assessed whether these variants were associated with risk of breast cancer in BRCA1 and BRCA2 mutation carriers. RESULTS: SNPs in five of the 14 candidate genes showed evidence of association with breast cancer risk for BRCA1 or BRCA2 carriers (P < 0.05). Notably, the minor alleles of two SNPs (rs7166081 and rs3825977) in high linkage disequilibrium (r² = 0.77), located at the SMAD3 locus (15q22), were each associated with increased breast cancer risk for BRCA2 mutation carriers (relative risk = 1.25, 95% confidence interval = 1.07 to 1.45, P(trend) = 0.004; and relative risk = 1.20, 95% confidence interval = 1.03 to 1.40, P(trend) = 0.018). CONCLUSIONS: This study provides evidence that the SMAD3 gene, which encodes a key regulatory protein in the transforming growth factor beta signalling pathway and is known to interact directly with BRCA2, may contribute to increased risk of breast cancer in BRCA2 mutation carriers. This finding suggests that genes with expression associated with BRCA1 and BRCA2 mutation status are enriched for the presence of common genetic modifiers of breast cancer risk in these populations.