Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk

Background Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk. Methods In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q Results The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p Conclusion These results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes.Peer reviewe

Polymorphisms in Stromal Genes and Susceptibility to Serous Epithelial Ovarian Cancer: A Report from the Ovarian Cancer Association Consortium

Peer reviewe

Epithelial-Mesenchymal Transition (EMT) Gene Variants and Epithelial Ovarian Cancer (EOC) Risk

Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single-nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A P-value <0.05 and a false discovery rate (FDR) <0.2 were considered statistically significant. In the larger dataset, GPC6/GPC5 rs17702471 was associated with the endometrioid subtype among Caucasians (odds ratio (OR) = 1.16, 95% CI = 1.07-1.25, P = 0.0003, FDR = 0.19), whereas F8 rs7053448 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), F8 rs7058826 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), and CAPN13 rs1983383 (OR = 0.79, 95% CI = 0.69-0.90, P = 0.0005, FDR = 0.12) were associated with combined invasive EOC among Asians. In silico functional analyses revealed that GPC6/GPC5 rs17702471 coincided with DNA regulatory elements. These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC.Other Research Uni

Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC)

Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovaries where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine single nucleotide polymorphisms (SNPs) in circadian genes BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant association was rs117104877 in BMAL1 (OR = 0.79, 95% CI = 0.68–0.90, p = 5.59 × 10−4]. Functional analysis revealed a significant down regulation of BMAL1 expression following cMYC overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of BMAL1 exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specifically BMAL1, may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways

MicroRNAs differentially expressed in prostate cancer of African-American and European-American men

African-American (AA) men have higher rates of prostate cancer incidence and mortality compared with European-American (EA) men. Although several socioeconomic and environmental factors may contribute to the disparity, recent studies suggest a biological component, including differential microRNA (miRNA) expression, to the disparity. miRNAs comprise a large family of about 22-nucleotide-long nonprotein coding RNAs that regulate gene expression posttranscriptionally and participate in the regulation of almost every known cellular process investigated to date. miRNAs have been associated with prostate cancer progression, and recent studies indicate that they are differentially expressed between AA and EA. They could therefore contribute, at least in part, to the disparity in prostate cancer between the two groups. In this review, existing evidence on differential miRNA expression between AA and EA prostate cancer patients or cell lines is summarized

Association between cumulative exposure to adverse childhood experiences and childhood obesity.

BackgroundExposure to adverse childhood experiences (ACEs) is associated with many childhood diseases and poor health outcomes in adulthood. However, the association with childhood obesity is inconsistent. We investigated the association between reported cumulative ACE score and body mass index (BMI) in a large sample of patients at a single institution.MethodsThis cross-sectional study included children aged 2-20 years that were screened in a general pediatrics clinic for ACEs utilizing the Center for Youth Wellness ACEs questionnaire between July 2017 and July 2018. Overall ACE score was categorized as 'no exposure' (score = 0), 'low exposure' (score = 1), and 'high exposure' (score≥ 2). BMI was categorized as overweight/obese (BMI percentile ≥ 85) or non-obese (BMI percentile ResultsOf the 948 patients included in the study, 30% (n = 314) were overweight/obese and 53% (n = 504) had no ACE exposure, 19% (n = 179) had low ACE exposure, and 28% (n = 265) had high ACE exposure. High ACE exposure was associated with increased odds of obesity (OR = 1.47, 95%CI = 1.07-2.03, p = 0.026). However, after adjusting for age, race/ethnicity, insurance type, and birth weight, the association attenuated and was null (OR = 1.01, 95%CI = 0.70-1.46, p = 0.97).ConclusionThe study findings may suggest an association between ACE and childhood obesity. However, the association attenuated after adjusting for age, race/ethnicity, insurance type, and birth weight. Larger prospective studies are warranted to better understand the association

Primary Dendritic Cells Phagocytose Cryptococcus neoformans via Mannose Receptors and Fcγ Receptor II for Presentation to T Lymphocytes

Different “professional” antigen-presenting cells (APC) have unique characteristics that favor or restrict presentation of microbial antigens to T cells, depending on the organism. Cryptococcus neoformans is a pathogenic yeast that presents unique challenges to APC, including its large size, its rigid cell wall, and its ability to stimulate T cells as a mitogen. T-cell proliferation in response to the C. neoformans mitogen (CnM) requires phagocytosis and processing of the organisms by accessory cells prior to presentation of CnM to T cells. Because of the requirement for uptake of the organism and more limited costimulatory requirements of mitogens, macrophages might be the most likely cellular source for the accessory cell. However, the present study demonstrates that a transiently adherent cell that was CD3(−), CD14(−), CD19(−), CD56(−), HLA-DR(+), and CD83(+) with a dendritic morphology, rather than monocyte-derived or tissue (alveolar) macrophages, was the most efficient APC for presentation of CnM. A large number of these cells bound and internalized the organism, and only a small number of dendritic cells were required for presentation of the mitogen to T cells. Further, the mannose receptor and Fcγ receptor II were required for presentation of C. neoformans, as blocking either of these receptors abrogated both uptake of C. neoformans and lymphocyte proliferation in response to CnM. These studies demonstrate the surprising fact that dendritic cells are the most efficient accessory cells for CnM

Hospital-associated venous thromboembolism in pediatrics: a systematic review and meta-analysis of risk factors and risk-assessment models

Hospital-associated venous thromboembolism, including deep vein thrombosis and pulmonary embolism, is increasing in pediatric centers. The objective of this work was to systematically review literature on pediatric hospital-acquired venous thromboembolism risk factors and risk-assessment models, to inform future prevention research. We conducted a literature search on pediatric venous thromboembolism risk via PubMed (1946-2014) and Embase (1980-2014). Data on risk factors and risk-assessment models were extracted from case-control studies, while prevalence data on clinical characteristics were obtained from registries, large (n>40) retrospective case series, and cohort studies. Meta-analyses were conducted for risk factors or clinical characteristics reported in at least three studies. Heterogeneity among studies was assessed with the Cochran Q test and quantified by the I(2) statistic. From 394 initial articles, 60 met the final inclusion criteria (20 case-control studies and 40 registries/large case series/cohort studies). Significant risk factors among case-control studies were: intensive care unit stay (OR: 2.14, 95% CI: 1.97-2.32); central venous catheter (OR: 2.12, 95% CI: 2.00-2.25); mechanical ventilation (OR: 1.56, 95%CI: 1.42-1.72); and length of stay in hospital (per each additional day, OR: 1.03, 95% CI: 1.03-1.03). Three studies developed/applied risk-assessment models from a combination of these risk factors. Fourteen significant clinical characteristics were identified through non-case-control studies. This meta-analysis confirms central venous catheter, intensive care unit stay, mechanical ventilation, and length of stay as risk factors. A few pediatric hospital-acquired venous thromboembolism risk scores have emerged employing these factors. Prospective validation is necessary to inform risk-stratified prevention trial

Predictors of postthrombotic syndrome in pediatric thrombosis: A systematic review and meta‐analysis of the literature

Background: Postthrombotic syndrome (PTS) is a significant complication of pediatric deep venous thrombosis (DVT). There is a gap in the understanding of the risk factors associated with the development of pediatric PTS preventing the early identification of those patients at greatest risk, and the development of risk-stratified interventions. Objectives: To conduct a systematic review and meta-analysis of the literature on prognostic factors for PTS development in pediatric patients. Methods: A systematic search of MEDLINE, EMBASE, and the Cochrane Library from 1960 to December 2018 was performed. Eligible studies reported at least one prognostic factor for PTS development in patients < 21 years of age with a radiographically confirmed DVT. To be included in the meta-analysis, prognostic factors had to be reported in at least three published studies. Results and conclusions: Twelve studies (n = 1160 patients) met criteria for inclusion. Ninety-three percent of patients with an extremity DVT (n = 1076) were assessed for PTS. PTS developed in 40% (n = 434) of these patients. Central venous catheter-associated DVT (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.08-2.98), complete veno-occlusion (OR, 1.89; 95% CI, 1.04-3.46), and incomplete DVT resolution (OR, 2.07; 95% CI, 1.4-3.07) were identified as candidate prognostic factors for pediatric PTS. These findings should be interpreted in the context of the heterogeneity of the included studies and the limitations of current pediatric PTS assessment tools. Further, the predictive value of these prognostic factors will need to be validated in future collaborative prospective multicenter studies that maximize the homogeneity of pediatric DVT patients