Molecular Study of Thyroid Cancer in World Trade Center Responders.
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ABSTRACT:
SUBMITTER: van Gerwen MAG
PROVIDER: S-EPMC6539993 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The gene expression approach has provided promising insights into the pathophysiology of PTSD. However, few studies used hypothesis-free transcriptome-wide expression approach. Transcriptome-wide expression study using RNA sequencing (RNA-Seq) of whole blood was conducted in 324 World Trade Center responders (201 with never, 81 current and 42 past PTSD). The current and never PTSD samples were randomly split to form both discovery (N=195) and replication (N=87) cohorts. Differentially expressed genes identified in RNA-Seq were used in pathway analysis and to create a polygenic expression score. There were 448 differentially expressed genes in the discovery cohort, of which 99 remained significant in the replication cohort, and 5 (FKBP5, NDUFA1, CCDC85B, SNORD54, SNORD46) showed >1.2-fold difference in expression consistently between the discovery and replication cohorts. Several enriched biological pathways were found, including glucocorticoid receptor signaling and immunity-related pathways, but were not significant following FDR correction. The gene expression score achieved sensitivity of 0.917 and specificity of 0.508 for identifying PTSD cases in the replication cohort. It was similar in current and past PTSD, with both groups scoring higher than trauma-exposed controls. We confirmed the role of FKBP5 in PTSD and identified four additional differentially expressed genes that may constitute biomarkers for this condition. Together with the pathway analysis results, these findings point to HPA-axis and immune dysregulation as key biological processes underpinning PTSD. A novel polygenic expression aggregate that differentiates PTSD patients from trauma-exposed controls might be a useful screening tool for research and clinical practice, if replicated in other populations.
2018-02-13 | GSE97356 | GEO
Project description:ObjectiveTo date, nearly 10,000 World Trade Center (WTC) responders have been diagnosed with at least one type of WTC-related cancer, and over 70 types of cancer have been related to WTC occupational exposure. Due to the observed latency period for malignancies, the WTC Health Program anticipates increases in rates of new cancer diagnoses. Given the growing number of cancer diagnoses in this population, there is an urgent need to develop a novel intervention to address the psychosocial needs of WTC responders with cancer. Meaning-centered psychotherapy (MCP) is a structured psychotherapeutic intervention originally developed to help patients with advanced cancer find and sustain meaning in life despite illness-related limitations. Existential distress and loss of meaning are critical and understudied elements of psychological health that have been widely overlooked among WTC responders with cancer.MethodWe have adapted MCP for WTC responders (MCP-WTC) for the treatment of WTC responders who have been diagnosed with WTC-certified cancers. MCP-WTC aims to target the complex crisis in meaning faced by those responders who responded to the 9/11 attacks and subsequently were diagnosed with cancer as a result of their service.ResultsWe describe the adaptation of MCP-WTC and the application of this intervention to meet the unique needs of those exposed to the terrorist attacks of September 11, 2001 (9/11), participated in the rescue, recovery, and clean-up effort at Ground Zero, and were diagnosed with WTC-related cancer. We highlight the novel aspects of this intervention which have been designed to facilitate meaning-making in the context of the patient's response to 9/11 and subsequent diagnosis of cancer.Significance of resultsThis work provides a rationale for MCP-WTC and the potential for this intervention to improve the quality of life of WTC responders and help these patients navigate life after 9/11 and cancer.
| S-EPMC7899195 | biostudies-literature
Project description:An excess incidence of prostate cancer has been identified among World Trade Center (WTC) responders. In this study, we hypothesized that WTC dust, which contained carcinogens and tumor-promoting agents, could facilitate prostate cancer development by inducing DNA damage, promoting cell proliferation, and causing chronic inflammation. We compared expression of immunologic and inflammatory genes using a NanoString assay on archived prostate tumors from WTC Health Program (WTCHP) patients and non-WTC patients with prostate cancer. Furthermore, to assess immediate and delayed responses of prostate tissue to acute WTC dust exposure via intratracheal inhalation, we performed RNA-seq on the prostate of normal rats that were exposed to moderate to high doses of WTC dust. WTC prostate cancer cases showed significant upregulation of genes involved in DNA damage and G2-M arrest. Cell-type enrichment analysis showed that Th17 cells, a subset of proinflammatory Th cells, were specifically upregulated in WTC patients. In rats exposed to WTC dust, we observed upregulation of gene transcripts of cell types involved in both adaptive immune response (dendritic cells and B cells) and inflammatory response (Th17 cells) in the prostate. Unexpectedly, genes in the cholesterol biosynthesis pathway were also significantly upregulated 30 days after acute dust exposure. Our results suggest that respiratory exposure to WTC dust can induce inflammatory and immune responses in prostate tissue. IMPLICATIONS: WTC-related prostate cancer displayed a distinct gene expression pattern that could be the result of exposure to specific carcinogens. Our data warrant further epidemiologic and cellular mechanistic studies to better understand the consequences of WTC dust exposure.Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/8/1605/F1.large.jpg.
| S-EPMC6684261 | biostudies-literature
Project description:BackgroundFollowing the September 11, 2001, attacks on the World Trade Center (WTC), thousands of workers were exposed to an array of toxins known to cause adverse health effects, including cancer. This study evaluates cancer incidence in the WTC Health Program General Responder Cohort occurring within 12 years post exposure.MethodsThe study population consisted of 28 729 members of the General Responder Cohort enrolled from cohort inception, July 2002 to December 31, 2013. Standardized incidence ratios (SIRs) were calculated with cancer case inclusion and follow-up starting post September 11, 2001 (unrestricted) and, alternatively, to account for selection bias, with case inclusion and follow-up starting 6 months after enrollment in the WTC Health Program (restricted). Case ascertainment was based on linkage with six state cancer registries. Under the restricted criterion, hazard ratios were estimated using multivariable Cox proportional hazards models for all cancer sites combined and for prostate cancer.ResultsRestricted analyses identified 1072 cancers in 999 responders, with elevations in cancer incidence for all cancer sites combined (SIR = 1.09, 95% confidence interval [CI] = 1.02 to 1.16), prostate cancer (SIR = 1.25, 95% CI = 1.11 to 1.40), thyroid cancer (SIR = 2.19, 95% CI = 1.71 to 2.75), and leukemia (SIR = 1.41, 95% CI = 1.01 to 1.92). Cancer incidence was not associated with any WTC exposure index (composite or individual) for all cancer sites combined or for prostate cancer.ConclusionOur analyses show statistically significant elevations in cancer incidence for all cancer sites combined and for prostate and thyroid cancers and leukemia. Multivariable analyses show no association with magnitude or type of exposure.
| S-EPMC7050150 | biostudies-literature
Project description:The gene expression approach has provided promising insights into the pathophysiology of posttraumatic stress disorder (PTSD). However, few studies used hypothesis-free transcriptome-wide approach to comprehensively understand gene expression underpinning PTSD. A transcriptome-wide expression study using RNA sequencing of whole blood was conducted in 324 World Trade Center responders (201 with never, 81 current, 42 past PTSD). Samples from current and never PTSD reponders were randomly split to form discovery (N = 195) and replication (N = 87) cohorts. Differentially expressed genes were used in pathway analysis and to create a polygenic expression score. There were 448 differentially expressed genes in the discovery cohort, of which 99 remained significant in the replication cohort, including FKBP5, which was found to be up-regulated in current PTSD regardless of the genotypes. Several enriched biological pathways were found, including glucocorticoid receptor signaling and immunity-related pathways, but these pathways did not survive FDR correction. The polygenic expression score computed by aggregating 30 differentially expressed genes using the elastic net algorithm achieved sensitivity/specificity of 0.917/0.508, respectively for identifying current PTSD in the replication cohort. Polygenic scores were similar in current and past PTSD, with both groups scoring higher than trauma-exposed controls without any history of PTSD. Together with the pathway analysis results, these findings point to HPA-axis and immune dysregulation as key biological processes underpinning PTSD. A novel polygenic expression aggregate that differentiates PTSD patients from trauma-exposed controls might be a useful screening tool for research and clinical practice, if replicated in other populations.
| S-EPMC5802695 | biostudies-literature
Project description:Existing work on proteomics has found common biomarkers that are altered in individuals with post-traumatic stress disorder (PTSD) and mild cognitive impairment (MCI). The current study expands our understanding of these biomarkers by profiling 276 plasma proteins with known involvement in neurobiological processes using the Olink Proseek Multiplex Platform in individuals with both PTSD and MCI compared to either disorder alone and with unaffected controls. Participants were World Trade Center (WTC) responders recruited through the Stony Brook WTC Health Program. PTSD and MCI were measured with the PTSD Checklist (PCL) and the Montreal Cognitive Assessment, respectively. Compared with unaffected controls, we identified 16 proteins associated with comorbid PTSD-MCI at P < 0.05 (six at FDR < 0.1), 20 proteins associated with PTSD only (two at FDR < 0.1), and 24 proteins associated with MCI only (one at FDR < 0.1), for a total of 50 proteins. The multiprotein composite score achieved AUCs of 0.84, 0.77, and 0.83 for PTSD-MCI, PTSD only, and MCI only versus unaffected controls, respectively. To our knowledge, the current study is the largest to profile a large set of proteins involved in neurobiological processes. The significant associations across the three case-group analyses suggest that shared biological mechanisms may be involved in the two disorders. If findings from the multiprotein composite score are replicated in independent samples, it has the potential to add a new tool to help classify both PTSD and MCI.
| S-EPMC7403297 | biostudies-literature
Project description:Gene expression has provided promising insights into the pathophysiology of posttraumatic stress disorder (PTSD), but specific regulatory transcriptomic mechanisms remain unknown. The current study addressed this limitation by analyzing transcriptome-wide RNA-Seq of whole blood samples from N=226 World Trade Center responders. The investigation focused on differential expression (DE) at gene, isoform, and alternative splicing (AS) levels associated with Posttraumatic Stress Disorder symptoms: total burden and its re-experiencing, avoidance, numbing, and hyperarousal subdimensions; and is the first study to characterize the AS landscape in PTSD. These dimensions were associated with 76, 1, 48, 15, and 49 genes, respectively (FDR<0.05). Similarly, they were associated with 103, 11, 0, 43, and 32 AS events. Avoidance differed the most from other dimensions with regard to DE genes, isoforms and AS correlates. Gene set enrichment analysis (GSEA) identified pathways involved in inflammatory and metabolic processes, which may have implications for the treatment of PTSD. Overall, findings shed a novel light on the wide range of transcriptomic alterations associated with PTSD at gene and AS levels. The DE analysis associated with PTSD subdimensions highlights the importance of studying PTSD symptom heterogeneity.
2021-06-03 | GSE164877 | GEO
Project description:Posttraumatic stress disorder (PTSD) has been linked to immunologic dysregulation. Gene expression profiling has emerged as a promising tool for understanding the pathophysiology of PTSD. However, to date, all but one gene expression study was based on whole blood or unsorted peripheral blood mononuclear cell (PBMC), a complex tissue consisting of several populations of cells. The objective of this study was to utilize RNA sequencing to simultaneously profile the gene-expression of four immune cell subpopulations in World Trade Center responders. Pathway analyses identified gene sets related to immune response and inflammation as being among the differentially expressed genes in PTSD, including mast cell activation and regulation in CD4T, interferon-beta production in CD8T, and neutrophil related gene sets in monocytes. These findings are suggestive that immune cell dysregulation involves gene expression in various cell populations.
2018-12-17 | GSE114407 | GEO
Project description:Previous epigenome-wide association studies (EWAS) of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) have been inconsistent. This may be due to small sample sizes, and measurement and tissue differences. The current two EWA analyses of 473 World Trade Center responders are the largest to date for both PTSD and MDD. These analyses investigated DNA methylation patterns and biological pathways influenced by differentially methylated genes associated with each disorder. Methylation was profiled on blood samples using Illumina 450?K Beadchip. Two EWA analyses compared current versus never PTSD, and current versus never MDD, adjusting for cell types and demographic confounders. Pathway and gene set enrichment analyses were performed to understand the complex biological systems of PTSD and MDD. No significant epigenome-wide associations were found for PTSD or MDD at an FDR P<0.05. The majority of genes with differential methylation at a suggestive threshold did not overlap between the two disorders. Pathways significant in PTSD included a regulator of synaptic plasticity, oxytocin signaling, cholinergic synapse and inflammatory disease pathways, while only phosphatidylinositol signaling and cell cycle pathways emerged in MDD. The failure of the current EWA analyses to detect significant epigenome-wide associations is in contrast with disparate findings from previous, smaller EWA and candidate gene studies of PTSD and MDD. Enriched gene sets involved in several biological pathways, including stress response, inflammation and physical health, were identified in PTSD, supporting the view that multiple genes play a role in this complex disorder.
| S-EPMC5537648 | biostudies-literature
Project description:Posttraumatic stress disorder (PTSD) is associated with shortened lifespan and healthspan, which suggests accelerated aging. Emerging evidence suggests that methylation age may be accelerated in PTSD. It is important to examine whether transcriptional age is also accelerated because transcriptome is highly dynamic, associated with age-related outcomes, and may offer greater insight into the premature aging in PTSD. This study is the first reported investigation of the relationship between transcriptional age and PTSD. Using RNA-Seq data from our previous study on 324 World Trade Center responders (201 never had PTSD, 81 with current PTSD, and 42 with past PTSD), as well as a transcriptional age calculator (RNAAgeCalc) recently developed by our group, we found that responders with current PTSD, compared with responders without a PTSD diagnosis, showed accelerated transcriptional aging (p = 0.0077) after adjustment for chronological age and race. We compared our results to the epigenetic aging results computed from several epigenetic clock calculators on matching DNA methylation data. GrimAge methylation age acceleration was also associated with PTSD diagnosis (p = 0.0097), and the results remained significant after adjustment for the proportions of immune cell types. PhenoAge, Hannum, and Horvath methylation age acceleration were not reliably related to PTSD. Both epigenetic and transcriptional aging may provide biological insights into the mechanisms underpinning aging in PTSD.
| S-EPMC8144188 | biostudies-literature