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<0.2 was applied to adjust for multiple comparisons. 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<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4). Conclusion These results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes

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

92 Honest Broker Tool to Automate Data Extraction from Clinical Research Data Warehouse

OBJECTIVES/GOALS: To describe an Honest Broker (HB) tool and workflow integrated with the Institutional Review Board (IRB) to automate requests, approvals and delivery of both de-identified and identified data extractions from a clinical research data warehouse (CRDW). METHODS/STUDY POPULATION: The HB tool has predefined domain tables and is closely integrated IRB for quick and easy review and approval. Investigators can access patient data using query tools, barcodes from biospecimens or build a query in TriNetX and provide the patient list as an input for the HB tool. For de-identified data extraction, the required data domain tables and date ranges can be selected and submitted in the HB tool. For identified data extractions, investigators with an approved IRB protocol can enter the protocol number and the approved date range in the HB tool. This request is automatically forwarded to the IRB for review. RESULTS/ANTICIPATED RESULTS: For de-identified data extraction, an email alert is automatically sent to the investigator once the data extract is completed. For identified data extraction, if IRB approves the request, an HB is immediately notified to release the data. Data release triggers two emails to the investigator: (1) a link to an encrypted zipped file with the requested data, and (2) a password to unlock the encrypted file. If the request is denied, the IRB sends an email to the investigator with the reason for denial and options for remediation. The entire HB workflow is accomplished in a secure environment with an audit trail from the initial data request to data download by the investigator. Since the launch of the HB tool, the time from data request to delivery is approximately an hour for deidentified data and 24 hrs for identified data. DISCUSSION/SIGNIFICANCE: The HB tool has increased successful data delivery in support of publications, grant submissions, and clinical trial recruitment. Optimization of data extraction from the CRDW through automation and integration with the IRB can minimize interaction with data analysts and IRB staff, thus accelerating the conduct of clinical research

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