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.

The Genes–Stemness–Secretome Interplay in Malignant Pleural Mesothelioma: Molecular Dynamics and Clinical Hints

“…Great efforts have been directed toward understanding the genetics behind what makes one more susceptible to the cancerogenic potential of asbestos. Particular focus has been placed on the genes involved in inflammatory infiltration, oxidative stress, chromosome instability, and response to treatments [ 25 ]. In this perspective, it has been reported that specific variants in three genes associated with iron metabolism, namely, ferritin, transferrin, and hephaestin, are significantly associated with protection against the development of MPM [ 26 , 27 ].…”