A transcriptomic analysis of data from patients with malignant pleural mesothelioma (MPM) has identified several novel genes that are differentially expressed in patients with documented asbestos exposure relative to those with no such exposure. This allows researchers to characterize a distinct gene expression profile for these patients.

The researchers say their work “lays the foundation for future investigations, including the development of biomarkers, with potential implications for the diagnostic and prognostic assessment of MPM.”

Published in Experimental and Molecular Pathology, the study was a collaborative effort between teams led by Professor Antonio Giordano, MD, PhD, Founder and Director of the Sbarro Health Research Organization and Professor at Temple University, and Professor Elisa Frullanti, PhD, Director of the Cancer Genomics & Systems Biology Lab and Professor of Genetics at the University of Siena.

Frullanti said the project was not just about cataloging genes. “It’s about constructing a molecular roadmap of asbestos-induced cancer development. With further validation, this could translate into real-world clinical applications.”

MPM is a rare and highly aggressive cancer primarily linked to asbestos exposure through inhalation of fibers in an occupational setting. The inhalation of the asbestos fibers causes chronic inflammation, driven by interactions between mesothelial cells and macrophages, releasing cytokines and reactive oxygen species (ROS), which perpetuate cellular damage. Recent studies suggest that ferroptosis, an iron-dependent form of cell death, may also play a role in MPM progression.

Despite significant advances in cancer treatment, people with MPM have a poor prognosis with a median survival of up to 18 months. Although some gene alterations, including those in tumor suppressor genes such as BAP1, CDKN2A, and NF2, are known to be involved in the pathogenesis of MPM, there is still limited understanding of the molecular mechanisms underlying asbestos-related carcinogenesis.

Giordano and team therefore used RNA sequencing data from patients with MPM in the MESO project of The Cancer Genome Atlas to identify gene expression profiles specific to mesothelioma patients with a documented history of asbestos exposure. In all, 13 samples from patients with asbestos exposure and 12 from unexposed patients were included in the study.

Differential gene expression analysis revealed that there were 25 genes that were up-regulated in patients with versus without asbestos exposure and 80 genes that were down-regulated.

“We were very surprised to see there were more gene expression downregulation than upregulation, almost three-to-one ratio,” said Giordano. “However, the types of genes upregulated versus those downregulated genes were very interesting.”

He told Inside Precision Medicine that the upregulated genes were mainly involved in responses to ROS and heavy metal exposure. “Asbestos has been shown to induce ROS as well as induce inflammation, so although this was expected it was interesting to see these groups of genes upregulated,” he remarked. “The downregulated genes were also interesting, as many of these gene products are involved in cellular signaling from the extracellular matrix, which usually have a role in metastasis.”

Indeed, the researchers report that functional enrichment analysis of the 25 upregulated genes highlighted several key biological processes, such as inorganic ion homeostasis, regulation of hydrogen peroxide catabolic processes, and detoxification pathways.

“These findings suggest that asbestos exposure disrupts essential cellular functions, particularly ion regulation and oxidative stress response,” they write. “Conversely, the analysis of the 80 downregulated genes revealed significant enrichment in cellular components, specifically the external side of the plasma membrane and the collagen-containing extracellular matrix. This supports the hypothesis that inhaling asbestos fibers could compromise cellular integrity and disrupt cell-matrix interactions.”

Among the genes differentially upregulated in people with asbestos exposure, MT1G are MMP1 are noteworthy as they are already well-documented in asbestos-induced carcinogenesis and could act as diagnostic biomarkers for asbestos exposure, the authors suggest.

Conversely, SNCA and RYR1 have not been previously linked to asbestos exposure but their upregulation requires further investigation due to their roles in ferroptosis, calcium homeostasis, and oxidative stress.

The differentially downregulated genes also gave a mixture of previously documented and novel insights. They included IGFBP7 and COL4A1, which have established roles in asbestos-related processes, and others, such as HEPH, that may show potential as a biomarker for asbestos-related carcinogenesis, despite currently limited direct evidence.

Although the findings shed some light on the molecular mechanisms of MPM, more needs to be done before the information can impact patient outcomes. Giordano suggests that artificial intelligence will help advance the field more rapidly. “The advent of artificial intelligence and its use in the biomedical sciences is helping us understand the complex patterns of gene expressions and genetic mutations required to initiate cancer, as well as determine those people who may be at heightened risk for developing MPM,” he said. “Our hope is that the use of this technology will quickly contribute to our understandings in this area.”

The researchers say that “future directions will include both in vitro and in vivo studies, focusing on the functional characterization of the highlighted genes.”

They conclude: “The ultimate goal is to identify novel diagnostic and prognostic biomarkers, along with candidate molecular targets to be evaluated in future studies, with potential implications in the clinical management of MPM.”