Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions.

To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value <5 × 10-8) and confirmed previously reported associations for 27 risk regions. Conditional analyses identified an additional 11 signals independent of the primary signal at six risk regions (p value <10-5). Fine mapping identified 4,008 CCVs in these regions, of which 1,452 CCVs were located in ovarian cancer-related chromatin marks with significant enrichment in active enhancers, active promoters, and active regions for CCVs from each EOC histotype. Transcriptome-wide association and colocalization analyses across histotypes using tissue-specific and cross-tissue datasets identified 86 candidate susceptibility genes in known EOC risk regions and 32 genes in 23 additional genomic regions that may represent novel EOC risk loci (false discovery rate <0.05). Finally, by integrating genome-wide HiChIP interactome analysis with transcriptome-wide association study (TWAS), variant effect predictor, transcription factor ChIP-seq, and motifbreakR data, we identified candidate gene-CCV interactions at each locus. This included risk loci where TWAS identified one or more candidate susceptibility genes (e.g., HOXD-AS2, HOXD8, and HOXD3 at 2q31) and other loci where no candidate gene was identified (e.g., MYC and PVT1 at 8q24) by TWAS. In summary, this study describes a functional framework and provides a greater understanding of the biological significance of risk alleles and candidate gene targets at EOC susceptibility loci identified by a genome-wide association study.

TREM1 disrupts myeloid bioenergetics and cognitive function in aging and Alzheimer disease mouse models.

Human genetics implicate defective myeloid responses in the development of late-onset Alzheimer disease. A decline in peripheral and brain myeloid metabolism, triggering maladaptive immune responses, is a feature of aging. The role of TREM1, a pro-inflammatory factor, in neurodegenerative diseases is unclear. Here we show that Trem1 deficiency prevents age-dependent changes in myeloid metabolism, inflammation and hippocampal memory function in mice. Trem1 deficiency rescues age-associated declines in ribose 5-phosphate. In vitro, Trem1-deficient microglia are resistant to amyloid-ß42 oligomer-induced bioenergetic changes, suggesting that amyloid-ß42 oligomer stimulation disrupts homeostatic microglial metabolism and immune function via TREM1. In the 5XFAD mouse model, Trem1 haploinsufficiency prevents spatial memory loss, preserves homeostatic microglial morphology, and reduces neuritic dystrophy and changes in the disease-associated microglial transcriptomic signature. In aging APPSwe mice, Trem1 deficiency prevents hippocampal memory decline while restoring synaptic mitochondrial function and cerebral glucose uptake. In postmortem Alzheimer disease brain, TREM1 colocalizes with Iba1+ cells around amyloid plaques and its expression is associated with Alzheimer disease clinical and neuropathological severity. Our results suggest that TREM1 promotes cognitive decline in aging and in the context of amyloid pathology.

Ventral temporal and posteromedial sulcal morphology in autism spectrum disorder.

Two parallel research tracks link the morphology of small and shallow indentations, or sulci, of the cerebral cortex with functional features of the cortex and human cognition, respectively. The first track identified a relationship between the mid-fusiform sulcus (MFS) in ventral temporal cortex (VTC) and cognition in individuals with Autism Spectrum Disorder (ASD). The second track identified a new sulcus, the inframarginal sulcus (IFRMS), that serves as a tripartite landmark within the posteromedial cortex (PMC). As VTC and PMC are structurally and functionally different in ASD, here, we integrated these two tracks and tested if there are morphological differences in VTC and PMC sulci in a sample of young (5-17 years old) male participants (50 participants with ASD and 50 neurotypical controls). Our approach replicates and extends recent findings in four ways. First, regarding replication, the standard deviation (STD) of MFS cortical thickness (CT) was increased in ASD. Second, MFS length was shorter in ASD. Third, the CT STD effect extended to other VTC and to PMC sulci. Fourth, additional morphological features of VTC sulci (depth, surface area, gray matter volume) and PMC sulci (mean CT) were decreased in ASD, including putative tertiary sulci, which emerge last in gestation and continue to develop after birth. To our knowledge, this study is the most extensive comparison of the sulcal landscape (including putative tertiary sulci) in multiple cortical expanses between individuals with ASD and NTs based on manually defined sulci at the level of individual hemispheres, providing novel targets for future studies of neurodevelopmental disorders more broadly.

Exome sequencing identifies breast cancer susceptibility genes and defines the contribution of coding variants to breast cancer risk.

Linkage and candidate gene studies have identified several breast cancer susceptibility genes, but the overall contribution of coding variation to breast cancer is unclear. To evaluate the role of rare coding variants more comprehensively, we performed a meta-analysis across three large whole-exome sequencing datasets, containing 26,368 female cases and 217,673 female controls. Burden tests were performed for protein-truncating and rare missense variants in 15,616 and 18,601 genes, respectively. Associations between protein-truncating variants and breast cancer were identified for the following six genes at exome-wide significance (P < 2.5 × 10-6): the five known susceptibility genes ATM, BRCA1, BRCA2, CHEK2 and PALB2, together with MAP3K1. Associations were also observed for LZTR1, ATR and BARD1 with P < 1 × 10-4. Associations between predicted deleterious rare missense or protein-truncating variants and breast cancer were additionally identified for CDKN2A at exome-wide significance. The overall contribution of coding variants in genes beyond the previously known genes is estimated to be small.

A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry.

BACKGROUND: Genome-wide studies of gene-environment interactions (G×E) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide G×E analysis of ~ 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer. METHODS: Analyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene-environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs. RESULTS: Assuming a 1 × 10-5 prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability < 15%, we identified two independent SNP-risk factor pairs: rs80018847(9p13)-LINGO2 and adult height in association with overall breast cancer risk (ORint = 0.94, 95% CI 0.92-0.96), and rs4770552(13q12)-SPATA13 and age at menarche for ER + breast cancer risk (ORint = 0.91, 95% CI 0.88-0.94). CONCLUSIONS: Overall, the contribution of G×E interactions to the heritability of breast cancer is very small. At the population level, multiplicative G×E interactions do not make an important contribution to risk prediction in breast cancer.

Análisis evolutivo de morbimortalidad en cirugía de urgencias durante la pandemia: comparación retrospectiva entre primera y segunda ola de COVID-19 / Evolutionary analysis of patient's morbidity and mortality in emergency surgical care during the pandemic: Retrospective comparison between first and second wave of COVID-19

Introducción: Desde el comienzo de la pandemia, la morbimortalidad en la atención urgente al paciente quirúrgico ha sido objeto de estudio. Sin embargo, la mayoría de los estudios compararon dicha variable con la propia de la época pre-COVID, obviando la evolución de la misma durante la propia pandemia. Con el objetivo de analizar este posible cambio, realizamos un estudio comparativo de morbimortalidad en cirugía de urgencias entre la primera y segunda ola de la pandemia en nuestro centro. Material y métodos: Estudio retrospectivo longitudinal que incluyó a todos los pacientes mayores de 18 años ingresados y/o intervenidos quirúrgicamente de forma urgente en los dos periodos de máxima incidencia (PMI) de infección por COVID-19 (1.er: 22/03/2020-31/05/2020; 2.° PMI: 26/08/2020-30/11/2020). Se analizó la incidencia de infección por SARS-CoV-2, el tratamiento recibido, la morbimortalidad precoz y los posibles factores de riesgo de complicaciones. Resultados: Se analizaron 173 pacientes (1.er: 66; 2.° PMI: 107). La incidencia de COVID-19 fue mayor en el segundo periodo (14,95% vs. 4,54%). La infección por SARS-CoV-2 se asoció a una mayor tasa de complicaciones, sin embargo, no se observaron diferencias estadísticamente significativas en la morbimortalidad general (p = 0,746) ni en la de los pacientes COVID positivos (p = 0,582) entre ambos periodos. El tratamiento quirúrgico se asoció con una menor tasa de complicaciones tanto en la primera (p = 0,006) como en la segunda ola (p = 0,014). Dicho tratamiento quirúrgico fue más frecuente en el segundo PMI (70,1 vs. 57,6%) aunque no se alcanzó la significación estadística al respecto de esta afirmación (p = 0,065).(AU)

Introduction: Since the beginning of the pandemic, morbidity and mortality in emergency care of surgical patients have been the subject of several studies. However, most of these have compared this variable with that of the pre-COVID period, ignoring its evolution during the pandemic itself. In order to analyze this possible change, we performed a comparative study of morbidity and mortality in emergency surgery between the first and second waves of the pandemic in our center. Material and methods: Retrospective longitudinal study including all patients over the age of 18 admitted and/or operated in the emergency setting in the two maximum incidence periods (MIP) of COVID-19 infection (1st MIP: 22/03/2020–31/05/2020; 2nd MIP: 26/08/2020–30/11/2020). The incidence of SARS-CoV-2 infection, treatment received, early morbidity and mortality and possible risk factors for complications were analyzed. Results: A total of 173 patients were analyzed (1st MIP: 66; 2nd MIP: 107). The incidence of COVID-19 was higher in the second period (14.95% vs. 4.54%). SARS-CoV-2 infection was associated with a higher rate of complications, however, no statistically significant differences were observed in morbimortality rate, either in the total sample (p = 0.746) or in patients with a positive COVID-19 test (p = 0.582) between both periods. Surgical treatment was found to be associated with a lower complication rate in both the first (p = 0.006) and second wave (p = 0.014), and it was more frequent in the second PMI (70.1 vs. 57.6%) although statistical significance was not reached (p = 0.065). (AU)

Clinical parameters affecting survival outcomes in patients with low-grade serous ovarian carcinoma: an international multicentre analysis.

BACKGROUND: Women with low-grade ovarian serous carcinoma (LGSC) benefit from surgical treatment; however, the role of chemotherapy is controversial. We examined an international database through the Ovarian Cancer Association Consortium to identify factors that affect survival in LGSC. METHODS: We performed a retrospective cohort analysis of patients with LGSC who had had primary surgery and had overall survival data available. We performed univariate and multivariate analyses of progression-free survival and overall survival, and generated Kaplan-Meier survival curves. RESULTS: Of the 707 patients with LGSC, 680 (96.2%) had available overall survival data. The patients' median age overall was 54 years. Of the 659 patients with International Federation of Obstetrics and Gynecology stage data, 156 (23.7%) had stage I disease, 64 (9.7%) had stage II, 395 (59.9%) had stage III, and 44 (6.7%) had stage IV. Of the 377 patients with surgical data, 200 (53.0%) had no visible residual disease. Of the 361 patients with chemotherapy data, 330 (91.4%) received first-line platinum-based chemotherapy. The median follow-up duration was 5.0 years. The median progression-free survival and overall survival were 43.2 months and 110.4 months, respectively. Multivariate analysis indicated a statistically significant impact of stage and residual disease on progression-free survival and overall survival. Platinum-based chemotherapy was not associated with a survival advantage. CONCLUSION: This multicentre analysis indicates that complete surgical cytoreduction to no visible residual disease has the most impact on improved survival in LGSC. This finding could immediately inform and change practice.

PET imaging of TREM1 identifies CNS-infiltrating myeloid cells in a mouse model of multiple sclerosis.

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS) that causes substantial morbidity and diminished quality of life. Evidence highlights the central role of myeloid lineage cells in the initiation and progression of MS. However, existing imaging strategies for detecting myeloid cells in the CNS cannot distinguish between beneficial and harmful immune responses. Thus, imaging strategies that specifically identify myeloid cells and their activation states are critical for MS disease staging and monitoring of therapeutic responses. We hypothesized that positron emission tomography (PET) imaging of triggering receptor expressed on myeloid cells 1 (TREM1) could be used to monitor deleterious innate immune responses and disease progression in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. We first validated TREM1 as a specific marker of proinflammatory, CNS-infiltrating, peripheral myeloid cells in mice with EAE. We show that the 64Cu-radiolabeled TREM1 antibody-based PET tracer monitored active disease with 14- to 17-fold higher sensitivity than translocator protein 18 kDa (TSPO)-PET imaging, the established approach for detecting neuroinflammation in vivo. We illustrate the therapeutic potential of attenuating TREM1 signaling both genetically and pharmacologically in the EAE mice and show that TREM1-PET imaging detected responses to an FDA-approved MS therapy with siponimod (BAF312) in these animals. Last, we observed TREM1+ cells in clinical brain biopsy samples from two treatment-naïve patients with MS but not in healthy control brain tissue. Thus, TREM1-PET imaging has potential for aiding in the diagnosis of MS and monitoring of therapeutic responses to drug treatment.

Manejo de quiste odontogénico glandular con rehabilitación implantológica guiada. Reporte de un caso / Management of glandular odontogenic cyst with guided implantologic rehabilitation. Case report

Resumen Objetivo: Describir el manejo de un caso de quiste odontogénico glandular, con tratamiento conservador, terapias adyuvantes y rehabilitación implantoasistida a los 7 años de seguimiento. Caso clínico: Se presenta un caso clínico de un paciente masculino con una lesión mandibular con diagnóstico de quiste odontogénico glandular. El tratamiento que se realizó fue una enucleación con tratamiento de superficie con solución de Carnoy y ostectomía periférica. Se realizó seguimiento clínico y radiográfico durante 7 años verificando ausencia de recidiva, momento en cual se realizó mediante planificación virtual la colocación de implantes con guías quirúrgicas de precisión para rehabilitación implanto asistida.

Abstract Aim: To describe the management of a case with a glandular odontogenic cyst, treated with a conservative treatment, adyuvant therapy and guided implantologic rehabilitation at 7 years of follow up. Clinical case: A case report of a male patient with a mandibular lesion with a diagnose of glandular odontogenic cyst is presented. The treatment that was performed was an enucleation with surface treatment with Carnoy's solution and peripheral ostectomy. Clinical and radiographic follow up was carried out for 7 years, verifying the absence of recurrence. At that time, it was done placement of implants with virtual planning and precision surgical guides for implant-assisted rehabilitation.

FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women.

Evidence from literature, including the BRIDGES study, indicates that germline protein truncating variants (PTVs) in FANCM confer moderately increased risk of ER-negative and triple-negative breast cancer (TNBC), especially for women with a family history of the disease. Association between FANCM missense variants (MVs) and breast cancer risk has been postulated. In this study, we further used the BRIDGES study to test 689 FANCM MVs for association with breast cancer risk, overall and in ER-negative and TNBC subtypes, in 39,885 cases (7566 selected for family history) and 35,271 controls of European ancestry. Sixteen common MVs were tested individually; the remaining rare 673 MVs were tested by burden analyses considering their position and pathogenicity score. We also conducted a meta-analysis of our results and those from published studies. We did not find evidence for association for any of the 16 variants individually tested. The rare MVs were significantly associated with increased risk of ER-negative breast cancer by burden analysis comparing familial cases to controls (OR = 1.48; 95% CI 1.07-2.04; P = 0.017). Higher ORs were found for the subgroup of MVs located in functional domains or predicted to be pathogenic. The meta-analysis indicated that FANCM MVs overall are associated with breast cancer risk (OR = 1.22; 95% CI 1.08-1.38; P = 0.002). Our results support the definition from previous analyses of FANCM as a moderate-risk breast cancer gene and provide evidence that FANCM MVs could be low/moderate risk factors for ER-negative and TNBC subtypes. Further genetic and functional analyses are necessary to clarify better the increased risks due to FANCM MVs.

Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry.

BACKGROUND: Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes. METHODS: We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry. RESULTS: In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 × 10-6) and AC058822.1 (P = 1.47 × 10-4), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C. CONCLUSIONS: Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 × 10-5), demonstrating the importance of diversifying study cohorts.

Evolutionary analysis of patient's morbidity and mortality in emergency surgical care during the pandemic: Retrospective comparison between first and second waves of COVID-19.

INTRODUCTION: Since the beginning of the pandemic, morbidity and mortality in emergency care of surgical patients have been the subject of several studies. However, most of these have compared this variable with that of the pre-COVID period, ignoring its evolution during the pandemic itself. In order to analyze this possible change, we performed a comparative study of morbidity and mortality in emergency surgery between the first and second waves of the pandemic in our center. METHODS: Retrospective longitudinal study including all patients over the age of 18 admitted and/or operated in the emergency setting in the two maximum incidence periods (MIP) of COVID-19 infection (1st MIP: 22/03/2020-31/05/2020; 2nd MIP: 26/08/2020-30/11/2020). The incidence of SARS-CoV-2 infection, treatment received, early morbidity and mortality and possible risk factors for complications were analyzed. RESULTS: A total of 173 patients were analyzed (1st MIP: 66; 2nd MIP: 107). The incidence of COVID-19 was higher in the second period (14.95% vs. 4.54%). SARS-CoV-2 infection was associated with a higher rate of complications; however, no statistically significant differences were observed in morbimortality rate, either in the total sample (P = .746) or in patients with a positive COVID-19 test (P = .582) between both periods. Surgical treatment was found to be associated with a lower complication rate in both the first (P = .006) and second waves (P = .014), and it was more frequent in the second MIP (70.1% vs 57.6%), although statistical significance was not reached (P = .065). CONCLUSIONS: No significant differences were observed in morbidity and mortality of patients admitted and/or operated in the emergency setting in the two periods of maximum incidence of SARS-CoV-2 at our center. Surgical treatment was associated with lower morbidity and mortality rates, and it was more frequent in the second MIP.

Performance of a fully-automated Lumipulse plasma phospho-tau181 assay for Alzheimer's disease.

BACKGROUND: The recent promise of disease-modifying therapies for Alzheimer's disease (AD) has reinforced the need for accurate biomarkers for early disease detection, diagnosis and treatment monitoring. Advances in the development of novel blood-based biomarkers for AD have revealed that plasma levels of tau phosphorylated at various residues are specific and sensitive to AD dementia. However, the currently available tests have shortcomings in access, throughput, and scalability that limit widespread implementation. METHODS: We evaluated the diagnostic and prognostic performance of a high-throughput and fully-automated Lumipulse plasma p-tau181 assay for the detection of AD. Plasma from older clinically unimpaired individuals (CU, n = 463) and patients with mild cognitive impairment (MCI, n = 107) or AD dementia (n = 78) were obtained from the longitudinal Stanford University Alzheimer's Disease Research Center (ADRC) and the Stanford Aging and Memory Study (SAMS) cohorts. We evaluated the discriminative accuracy of plasma p-tau181 for clinical AD diagnosis, association with amyloid ß peptides and p-tau181 concentrations in CSF, association with amyloid positron emission tomography (PET), and ability to predict longitudinal cognitive and functional change. RESULTS: The assay showed robust performance in differentiating AD from control participants (AUC 0.959, CI: 0.912 to 0.990), and was strongly associated with CSF p-tau181, CSF Aß42/Aß40 ratio, and amyloid-PET global SUVRs. Associations between plasma p-tau181 with CSF biomarkers were significant when examined separately in Aß+ and Aß- groups. Plasma p-tau181 significantly increased over time in CU and AD diagnostic groups. After controlling for clinical diagnosis, age, sex, and education, baseline plasma p-tau181 predicted change in MoCA overall and change in CDR Sum of Boxes in the AD group over follow-up of up to 5 years. CONCLUSIONS: This fully-automated and available blood-based biomarker assay therefore may be useful for early detection, diagnosis, prognosis, and treatment monitoring of AD.

[Evolutionary analysis of patient´s morbidity and mortality in emergency surgical care during the pandemic: retrospective comparison between the first and second waves of COVID-19.] / Análisis evolutivo de morbimortalidad en cirugía de urgencias durante la pandemia: comparación retrospectiva entre primera y segunda ola de COVID-19.

INTRODUCTION: Since the beginning of the pandemic, morbidity and mortality in emergency care of surgical patients have been the subject of several studies. However, most of these have compared this variable with that of the pre-COVID period, ignoring its evolution during the pandemic itself. In order to analyze this possible change, we performed a comparative study of morbidity and mortality in emergency surgery between the first and second waves of the pandemic in our center. MATERIAL AND METHODS: Retrospective longitudinal study including all patients over the age of 18 admitted and/or operated in the emergency setting in the two maximum incidence periods (MIP) of COVID-19 infection (1st MIP: 22/03/2020-31/05/2020; 2nd MIP: 26/08/2020-30/11/2020). The incidence of SARS-CoV-2 infection, treatment received, early morbidity and mortality and possible risk factors for complications were analyzed. RESULTS: A total of 173 patients were analyzed (1st MIP: 66; 2nd MIP: 107). The incidence of COVID-19 was higher in the second period (14.95% vs. 4.54%). SARS-CoV-2 infection was associated with a higher rate of complications, however, no statistically significant differences were observed in morbimortality rate, either in the total sample (p=0.746) or in patients with a positive COVID-19 test (p=0.582) between both periods. Surgical treatment was found to be associated with a lower complication rate in both the first (p=0.006) and second wave (p=0.014), and it was more frequent in the second PMI (70.1 vs. 57.6%) although statistical significance was not reached (p= 0.065). CONCLUSIONS: No significant differences were observed in morbimortality of patients admitted and/or operated in the emergency setting in the two periods of maximum incidence of SARS-CoV-2 in our center. Surgical treatment was associated with a lower morbimortality rate, and it was more frequent in the second MIP.

OGG1 Inhibition Triggers Synthetic Lethality and Enhances The Effect of PARP Inhibitor Olaparib in BRCA1-Deficient TNBC Cells.

Background: PARP1 plays a critical role in the base excision repair (BER) pathway, and PARP1 inhibition leads to specific cell death, through a synthetic lethal interaction, in the context of BRCA1/2 deficiency. To date, up to five different PARP inhibitors (PARPi), have been approved, nevertheless, the acquisition of resistance to PARPi is common and there is increasing interest in enhancing responses and expand their use to other tumour types. Methods: We hypothesized that other BER members could be additional synthetic lethal partners with mutated BRCA genes. To test this, we decided to evaluate the glycosylase OGG1 as a potential candidate, by treating BRCA1 proficient and deficient breast cancer cells with PARPi olaparib and the OGG1 inhibitor TH5478. Results: Knocking out BRCA1 in triple-negative breast cancer cell lines causes hypersensitivity to the OGG1 inhibitor TH5487. Besides, TH5487 enhances the sensitivity to the PARP inhibitor olaparib, especially in the context of BRCA1 deficiency, reflecting an additive interaction. Discussion: These results provide the first evidence that OGG1 inhibition is a promising new synthetic lethality strategy in BRCA1-deficient cells, and could lead to a new framework for the treatment of hereditary breast and ovarian cancer.

CDK5RAP3, a New BRCA2 Partner That Regulates DNA Repair, Is Associated with Breast Cancer Survival.

BRCA2 is essential for homologous recombination DNA repair. BRCA2 mutations lead to genome instability and increased risk of breast and ovarian cancer. Similarly, mutations in BRCA2-interacting proteins are also known to modulate sensitivity to DNA damage agents and are established cancer risk factors. Here we identify the tumor suppressor CDK5RAP3 as a novel BRCA2 helical domain-interacting protein. CDK5RAP3 depletion induced DNA damage resistance, homologous recombination and single-strand annealing upregulation, and reduced spontaneous and DNA damage-induced genomic instability, suggesting that CDK5RAP3 negatively regulates double-strand break repair in the S-phase. Consistent with this cellular phenotype, analysis of transcriptomic data revealed an association between low CDK5RAP3 tumor expression and poor survival of breast cancer patients. Finally, we identified common genetic variations in the CDK5RAP3 locus as potentially associated with breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. Our results uncover CDK5RAP3 as a critical player in DNA repair and breast cancer outcomes.

Polygenic risk modeling for prediction of epithelial ovarian cancer risk.

Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.