Abstract
Lung cancer remains the leading cause of cancer death globally, with lung adenocarcinoma (LUAD) being its most prevalent subtype. Due to the heterogeneity of LUAD, patients given the same treatment regimen may have different responses and clinical outcomes. Therefore, identifying new subtypes of LUAD is important for predicting prognosis and providing personalized treatment for patients. Pyroptosis-related genes play an essential role in anticancer, but there is limited research investigating pyroptosis in LUAD. In this study, 33 pyroptosis gene expression profiles and clinical information were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. By bioinformatics and machine learning analyses, we identified novel subtypes of LUAD based on 10 pyroptosis-related genes and further validated them in the GEO dataset, with machine learning models performing up to an AUC of 1 for classifying in GEO. A web-based tool was established for clinicians to use our clustering model (http://www.aimedicallab.com/tool/aiml-subphe-luad.html). LUAD patients were clustered into 3 subtypes (A, B, and C), and survival analysis showed that B had the best survival outcome and C had the worst survival outcome. The relationships between pyroptosis gene expression and clinical characteristics were further analyzed in the three molecular subtypes. Immune profiling revealed significant differences in immune cell infiltration among the three molecular subtypes. GO enrichment and KEGG pathway analyses were performed based on the differential genes of the three subtypes, indicating that differentially expressed genes (DEGs) were involved in multiple cellular and biological functions, including RNA catabolic process, mRNA catabolic process, and pathways of neurodegeneration-multiple diseases. Finally, we developed an 8-gene prognostic model that accurately predicted 1-, 3-, and 5-year overall survival. In conclusion, pyroptosis-related genes may play a critical role in LUAD, and provide new insights into the underlying mechanisms of LUAD.
Highlights
Lung cancer is the second most prevalent cancer worldwide, and remains the leading cause of cancer death globally (Sung et al, 2021)
lung adenocarcinoma (LUAD) patients in the The Cancer Genome Atlas (TCGA) dataset were divided into three different molecular subtypes (A, B, and C-cluster) by consensus clustering analysis based on 33 pyroptosis-related genes
After judging the molecular subtypes of each LUAD patient using the CatBoost model, the outcomes corresponding to the three molecular subtypes and the classification effect of the CatBoost model were explored by survival analysis and t-distributed stochastic neighbor embedding (t-SNE) analysis, respectively
Summary
Lung cancer is the second most prevalent cancer worldwide, and remains the leading cause of cancer death globally (Sung et al, 2021). Various blocking immune checkpoint therapies such as programmed cell death protein 1 (PD1, PDCD1) and T-lymphocyte-associated antigen 4 (CTLA4) have shown significant efficacy in the treatment of LUAD (Topalian et al, 2016). A proportion of LUAD patients were resistant to chemotherapy, immunotherapy, or targeted therapy, leading to cancer relapse or death (Zhang Y. et al, 2020). The reason why these therapies failed in some patients is partly due to the heterogeneous of LUAD. It is significant to identify novel subtypes of LUAD, to predict prognosis and provide personalized treatment for patients
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