Genomic Instability-Related LncRNA Signature Predicts the Prognosis and Highlights LINC01614 Is a Tumor Microenvironment-Related Oncogenic lncRNA of Papillary Thyroid Carcinoma

Background Genomic instability (GI) is among the top ten characteristics of malignancy. Long non-coding RNAs (lncRNAs) are promising cancer biomarkers that are reportedly involved in GI. So far, the clinical value of GI-related lncRNAs (GIlncs) in papillary thyroid cancer (PTC) has not been clarified. Methods Integrative analysis of lncRNA expression and somatic mutation profiles was performed to identify GIlncs. Analysis of differentially expressed lncRNAs in the group with high- and low- cumulative number of somatic mutations revealed significant GIlncs in PTC. Univariate and multivariate Cox proportional hazard regression analyses were performed to identify hub-GIlncs. Results A computational model based on four lncRNAs (FOXD2-AS1, LINC01614, AC073257.2, and AC005082.1) was identified as a quantitative index using an in-silicon discovery cohort. GILS score was significantly associated with poor prognosis, as validated in the TCGA dataset and further tested in our local RNA-Seq cohort. Moreover, a combination of clinical characteristics and the composite GILS-clinical prognostic nomogram demonstrates satisfactory discrimination and calibration. Furthermore, the GILS score and FOXD2-AS1, LINC01614, AC073257.2, and AC005082.1 were also associated with driver mutations and multiple clinical-pathological variables, respectively. Moreover, RNA-Seq confirmed the expression patterns of FOXD2-AS1, LINC01614, AC073257.2, and AC005082.1 in PTC and normal thyroid tissues. Biological experiments demonstrated that downregulated or overexpressed LINC01614 affect PTC cell proliferation, migration, and invasion in vitro. Activation of the stromal and immune cell infiltration was also observed in the high LINC01614 group in the PTC microenvironment. Conclusion In summary, we identified a signature for clinical outcome prediction in PTC comprising four lncRNAs associated with GI. A better understanding of the GI providing an alternative evaluation of the progression risk of PTC. Our study also demonstrated LINC01614 as a novel oncogenic lncRNA and verified its phenotype in PTC.

Automated summary

By analyzing lncRNA expression and somatic mutation profiles, significant GI-related lncRNAs in PTC were identified. A computational model based on four lncRNAs was established as a quantitative index for poor prognosis prediction. The study demonstrated the potential of lncRNAs as cancer biomarkers and provided insights into the biological mechanisms of GI in PTC.