Construction of subtype classifiers and validation of a prognostic risk model based on hypoxia-associated lncRNAs for lung adenocarcinoma.

Background: Studies have shown that long non-coding RNAs (lncRNAs) are found to be hypoxia-regulated lncRNAs in cancer. Lung adenocarcinoma (LUAD) is the leading cause of cancer death worldwide, and despite early surgical removal, has a poor prognosis and a high recurrence rate. Thus, we aimed to identify subtype classifiers and construct a prognostic risk model using hypoxia-associated long noncoding RNAs (hypolncRNAs) for LUAD.

Methods: Clinical data of LUAD samples with prognosis information obtained from the Gene Expression Omnibus (GEO), acted as validation dataset, and The Cancer Genome Atlas (TCGA) databases, served as training dataset, were used to screen hypolncRNAs in each dataset by univariate Cox regression analysis; the intersection set was used for subsequent analyses. Unsupervised clustering analysis was performed based on the expression of hypolncRNAs using the 'ConsensuClusterPlus' package. The tumor microenvironment (TME) was compared between LUAD subgroups by analyzing the expression of immune cell infiltration, immune components, stromal components, immune checkpoints, and chemokine secretion. To identify robust prognostically associated hypolncRNAs and construct a risk score model, multivariate Cox regression analysis was performed.

Results: A total of 14 hypolncRNAs were identified. Based on the expression of these hypolncRNAs, patients with LUAD were classified into three hypolncRNA-regulated subtypes. The three subtypes differed significantly in immune cell infiltration, stromal score, specific immune checkpoints, and secretion of chemokines and their receptors. The Tumor Immune Dysfunction and Exclusion (TIDE) scores and myeloid-derived suppressor cell (MDSC) scores were also found to differ significantly among the three hypolncRNA-regulated subtypes. Four of the 14 hypolncRNAs were used to construct a signature to distinguish the overall survival (OS) in TCGA dataset (P<0.0001) and GEO dataset (P=0.0032) and sensitivity to targeted drugs in patients at different risks of LUAD.

Conclusions: We characterized three regulatory subtypes of hypolncRNAs with different TMEs. We developed a signature based on hypolncRNAs, contributing to the development of personalized therapy and representing a new potential therapeutic target for LUAD.