Abstract
Simple SummaryDifferences in epidemiological and clinical patterns of lung adenocarcinoma have been described between male and female patients. Our study aimed to assess the molecular mechanisms underlying those differences through functional profiling and meta-analysis of lung adenocarcinoma expression datasets. We discovered an overrepresentation of terms related to acute inflammatory responses in female patients, suggesting an increase in certain cell populations, such as T CD8+ cells, and in interleukin production. We also identified purinergic signaling and lipid metabolism as relevant upregulated functional groups in female lung adenocarcinoma samples. Overall, we identified molecular processes and pathways that will aid the understanding of the differential clinical patterns described in lung adenocarcinoma in male and female patients and provide new pathways for the discovery of novel biomarkers and therapeutic targets.While studies have established the existence of differences in the epidemiological and clinical patterns of lung adenocarcinoma between male and female patients, we know relatively little regarding the molecular mechanisms underlying such sex-based differences. In this study, we explore said differences through a meta-analysis of transcriptomic data. We performed a meta-analysis of the functional profiling of nine public datasets that included 1366 samples from Gene Expression Omnibus and The Cancer Genome Atlas databases. Meta-analysis results from data merged, normalized, and corrected for batch effect show an enrichment for Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways related to the immune response, nucleic acid metabolism, and purinergic signaling. We discovered the overrepresentation of terms associated with the immune response, particularly with the acute inflammatory response, and purinergic signaling in female lung adenocarcinoma patients, which could influence reported clinical differences. Further evaluations of the identified differential biological processes and pathways could lead to the discovery of new biomarkers and therapeutic targets. Our findings also emphasize the relevance of sex-specific analyses in biomedicine, which represents a crucial aspect influencing biological variability in disease.
Highlights
Lung cancer is the most frequently diagnosed cancer and the leading cause of cancerrelated death worldwide, representing 18.4% of all cancer deaths [1]
We organized our findings into three sections: the first describes the studies evaluated and selected in the systematic review; the second section reports on the results of the bioinformatic analysis of each of these selected studies as follows: (i) exploratory analysis, (ii) differential expression, and (iii) functional characterization; while the third section presents the results of the differential functional profiling by sex
“Metabolism- Nucleic acids metabolism and signaling” was the Functions second most abundant functional group upregulated in female lung adenocarcinoma We discovered that 43.88% of detected functions related to the immune response patients, comprising 8.63% of the altered functions
Summary
Lung cancer is the most frequently diagnosed cancer and the leading cause of cancerrelated death worldwide, representing 18.4% of all cancer deaths [1]. Domestic biomass fuels, asbestos, and radon represent the most relevant lung cancer risk factors [1,2,3]; as has become evident from studies of other cancer types, sex-based differences (sexual dimorphisms) may have significant relevance in lung cancer [1,4,5]. While lung cancer incidence worldwide is higher in men, there exists an increasing trend in women that cannot be solely explained by tobacco consumption [1,2]. Studies have reported sex-dependent differences in estrogen receptors and their impact on lung cancer [8,9,10]; conflicting results have attributed lung cancer susceptibility in women to genetic variants, hormonal factors, molecular abnormalities, and oncogenic viruses [3,11,12,13].
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