Identification of the Prognostic Significance of Somatic Mutation-Derived LncRNA Signatures of Genomic Instability in Lung Adenocarcinoma

Background: Lung adenocarcinoma (LUAD) is a highly heterogeneous tumor with substantial somatic mutations and genome instability, which are emerging hallmarks of cancer. Long non-coding RNAs (lncRNAs) are promising cancer biomarkers that are reportedly involved in genomic instability. However, the identification of genome instability-related lncRNAs (GInLncRNAs) and their clinical significance has not been investigated in LUAD.

Methods: We determined GInLncRNAs by combining somatic mutation and transcriptome data of 457 patients with LUAD and probed their potential function using co-expression network and Gene Ontology (GO) enrichment analyses. We then filtered GInLncRNAs by Cox regression and LASSO regression to construct a genome instability-related lncRNA signature (GInLncSig). We subsequently evaluated GInLncSig using correlation analyses with mutations, external validation, model comparisons, independent prognostic significance analyses, and clinical stratification analyses. Finally, we established a nomogram for prognosis prediction in patients with LUAD and validated it in the testing set and the entire TCGA dataset.

Results: We identified 161 GInLncRNAs, of which seven were screened to develop a prognostic GInLncSig model (LINC01133, LINC01116, LINC01671, FAM83A-AS1, PLAC4, MIR223HG, and AL590226.1). GInLncSig independently predicted the overall survival of patients with LUAD and displayed an improved performance compared to other similar signatures. Furthermore, GInLncSig was related to somatic mutation patterns, suggesting its ability to reflect genome instability in LUAD. Finally, a nomogram comprising the GInLncSig and tumor stage exhibited improved robustness and clinical practicability for predicting patient prognosis.

Conclusion: Our study identified a signature for prognostic prediction in LUAD comprising seven lncRNAs associated with genome instability, which may provide a useful indicator for clinical stratification management and treatment decisions for patients with LUAD.