Dataset Information

Variant Enrichment Analysis to Explore Pathways Disruption in a Necropsy Series of Asbestos-Exposed Shipyard Workers.

ABSTRACT: The variant enrichment analysis (VEA), a recently developed bioinformatic workflow, has been shown to be a valuable tool for whole-exome sequencing data analysis, allowing finding differences between the number of genetic variants in a given pathway compared to a reference dataset. In a previous study, using VEA, we identified different pathway signatures associated with the development of pulmonary toxicities in mesothelioma patients treated with radical hemithoracic radiation therapy. Here, we used VEA to discover novel pathways altered in individuals exposed to asbestos who developed or not asbestos-related diseases (lung cancer or mesothelioma). A population-based autopsy study was designed in which asbestos exposure was evaluated and quantitated by investigating objective signs of exposure. We selected patients with similar exposure to asbestos. Formalin-fixed paraffin-embedded (FFPE) tissues were used as a source of DNA and whole-exome sequencing analysis was performed, running VEA to identify potentially disrupted pathways in individuals who developed thoracic cancers induced by asbestos exposure. By using VEA analysis, we confirmed the involvement of pathways considered as the main culprits for asbestos-induced carcinogenesis: oxidative stress and chromosome instability. Furthermore, we identified protective genetic assets preserving genome stability and susceptibility assets predisposing to a worst outcome.

SUBMITTER: Crovella S

PROVIDER: S-EPMC9654668 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Variant Enrichment Analysis to Explore Pathways Disruption in a Necropsy Series of Asbestos-Exposed Shipyard Workers.

Crovella Sergio S Moura Ronald Rodrigues RR Brandão Lucas L Vita Francesca F Schneider Manuela M Zanconati Fabrizio F Finotto Luigi L Zacchi Paola P Zabucchi Giuliano G Borelli Violetta V

International journal of molecular sciences 20221107 21

The variant enrichment analysis (VEA), a recently developed bioinformatic workflow, has been shown to be a valuable tool for whole-exome sequencing data analysis, allowing finding differences between the number of genetic variants in a given pathway compared to a reference dataset. In a previous study, using VEA, we identified different pathway signatures associated with the development of pulmonary toxicities in mesothelioma patients treated with radical hemithoracic radiation therapy. Here, we ...[more]

PMID: 36362413

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Project description:BackgroundThe current reference test for the detection of respiratory abnormalities in asbestos-exposed workers is spirometry. However, spirometry has several shortcomings that greatly affect the efficacy of current asbestos control programs. The forced oscillation technique (FOT) represents the current state-of-the-art technique in the assessment of lung function. This method provides a detailed analysis of respiratory resistance and reactance at different oscillatory frequencies during tidal breathing. Here, we evaluate the FOT as an alternative method to standard spirometry for the early detection and quantification of respiratory abnormalities in asbestos-exposed workers.Methodology/principal findingsSeventy-two subjects were analyzed. The control group was composed of 33 subjects with a normal spirometric exam who had no history of smoking or pulmonary disease. Thirty-nine subjects exposed to asbestos were also studied, including 32 volunteers in radiological category 0/0 and 7 volunteers with radiological categories of 0/1 or 1/1. FOT data were interpreted using classical parameters as well as integer (InOr) and fractional-order (FrOr) modeling. The diagnostic accuracy was evaluated by investigating the area under the receiver operating characteristic curve (AUC). Exposed workers presented increased obstruction (resistance p<0.001) and a reduced compliance (p<0.001), with a predominance of obstructive changes. The FOT parameter changes were correlated with the standard pulmonary function analysis methods (R = -0.52, p<0.001). Early respiratory abnormalities were identified with a high diagnostic accuracy (AUC = 0.987) using parameters obtained from the FrOr modeling. This accuracy was significantly better than those obtained with classical (p<0.001) and InOr (p<0.001) model parameters.ConclusionsThe FOT improved our knowledge about the biomechanical abnormalities in workers exposed to asbestos. Additionally, a high diagnostic accuracy in the diagnosis of early respiratory abnormalities in asbestos-exposed workers was obtained. This makes the FOT particularly useful as a screening tool in the context of asbestos control and elimination. Moreover, it can facilitate epidemiological research and the longitudinal follow-up of asbestos exposure and asbestos-related diseases.

Project description:ImportanceIt is important to determine what frequencies and auditory perceptual measures are the most sensitive early indicators of noise-induced hearing impairment.ObjectivesTo examine whether hearing loss among shipyard workers increases more rapidly at extended high frequencies than at clinical frequencies and whether subtle auditory processing deficits are present in those with extensive noise exposure but little or no hearing loss.Design, setting, and participantsThis cross-sectional study collected audiometric data (0.25-16 kHz), survey questionnaires, and noise exposure levels from 7890 shipyard workers in a Shanghai shipyard from 2015 to 2019. Worsening hearing loss was evaluated in the group with hearing loss. Speech processing and temporal processing were evaluated in 610 participants with noise exposure and clinically normal hearing to identify early biomarkers of noise-induced hearing impairment. Data analysis was conducted from November to December 2020.Main outcomes and measuresLinear regression was performed to model the increase in hearing loss as function of cumulative noise exposure and compared with a group who were monitored longitudinally for 4 years. Auditory processing tests included speech-in-noise tests, competing sentence tests, dichotic listening tests, and gap detection threshold tests and were compared with a control group without history of noise exposure.ResultsOf the 5539 participants (median [interquartile range (IQR)] age, 41.0 [34.0-47.0] years; 3861 [86.6%] men) included in the cross-sectional analysis, 4459 (80.5%) were hearing loss positive and 1080 (19.5%) were hearing loss negative. In younger participants (ie, ≤40 years), the maximum rate of increase in hearing loss was 0.40 (95% CI, 0.39-0.42) dB per A-weighted dB-year (dB/dBA-year) at 12.5 kHz, higher than the growth rates of 0.36 (95% CI, 0.35-0.36) dB/dBA-year at 4 kHz, 0.32 (95% CI, 0.31-0.33) dB/dBA-year at 10 kHz, 0.31 (95% CI, 0.30-0.31) dB/dBA-year at 6 kHz, 0.27 (95% CI, 0.26-0.27) dB/dBA-year at 3 kHz, and 0.27 (95% CI, 0.27-0.28) dB/dBA-year at 8 kHz. In the 4-year longitudinal analysis of hearing loss among 403 participants, the mean (SD) annual deterioration in hearing was 2.70 (2.98) dB/y at 12.5 kHz, almost twice as that observed at lower frequencies (eg, at 3kHz: 1.18 [2.15] dB/y). The auditory processing scores of participants with clinically normal hearing and a history of noise exposure were significantly lower than those of control participants (eg, median [IQR] score on speech-in-noise test, noise-exposed group 1 vs control group: 0.63 [0.55-0.66] vs 0.78 [0.76-0.80]; P < .001).Conclusions and relevanceThese findings suggest that the increase in hearing loss among shipyard workers was more rapid at 12.5 kHz than at other frequencies; workers with clinically normal hearing but high cumulative noise exposure are likely to exhibit deficits in speech and temporal processing.

Project description:ObjectivesThe knowledge of past asbestos exposure may lead to chronic psychological strain. In addition, the information about an increased cancer risk can place a psychological burden on individuals triggering mental health symptoms of depression or anxiety. This applies in particular to individuals with non-malignant asbestos-related disease (ARD) such as lung fibrosis and pleural thickening with or without lung function impairment. ARDs with or without lung function impairment may develop even years after exposure cessation. Therefore, the aim of the present study was to test for our cohort whether non-malignant ARD and lung function impairment have differential effects on mental health and psychological strain.DesignCross-sectional study.Participants and settingOverall, 612 male participants (mean age=66.2 years, SD=9.5) attending a surveillance programme for ARDs received routine examinations including lung function testing (24% refused to fill in the psychological questionnaire) at a German university hospital study centre from August 2008 to August 2013.Outcome measuresUsing multiple hierarchical regression analysis, ARD diagnosis and lung function impairment were used to predict psychological health as measured with validated questionnaires for depression and anxiety. Psychological strain was operationalised by intrusive thoughts and specific fear of cancer.ResultsThe strongest predictor for mental health was obstructive functional impairment (eg, anxiety: β=0.22, p<0.001). Psychological strain was predicted by the presence of a non-malignant ARD (eg, intrusive thoughts: β=0.17, p=0.003).ConclusionsThe presence of mental health symptoms is associated with ventilation disturbances, whereas the knowledge of an already initiated morphological change-caused by asbestos exposure-is primarily associated with psychological strain. Specifically, the affected individuals are more prone to intrusive thoughts and specific fear of asbestos-related cancer. As an implication, physicians should be sensitised about possible consequences of risk communication and functional impairment to counteract excessive fear or anxiety.

Dataset Information

Variant Enrichment Analysis to Explore Pathways Disruption in a Necropsy Series of Asbestos-Exposed Shipyard Workers.

Publications

Variant Enrichment Analysis to Explore Pathways Disruption in a Necropsy Series of Asbestos-Exposed Shipyard Workers.

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