Abstract
BackgroundGenomic 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.MethodsIntegrative 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.ResultsA 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.ConclusionIn 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.
Highlights
Papillary thyroid cancer (PTC) is the most common type of thyroid cancer, with heterogeneous biological behavior and a favorable prognosis [1,2,3]
We identified 558 GI-related lncRNAs (GIlncs) were differentially expressed between the two groups (Supplementary Table S1), among which 533 upregulated and 25 downregulated Long non-coding RNAs (lncRNAs) in the genomic unstable-like (GU-like) group (Figure 2A)
To investigate the potential functions of the GIlncs, we explored the protein-coding genes (PCGs), which were coexpressed with lncRNA
Summary
Papillary thyroid cancer (PTC) is the most common type of thyroid cancer, with heterogeneous biological behavior and a favorable prognosis [1,2,3]. In a retrospective study of PTC with 27 years of median follow-up times, the recurrence rate and PTC-specific death rate were 28% and 9%, respectively [4]. The overall prognosis of most PTC patients was satisfactory, there was still a small part of PTC patients having aggressive characteristics, and even after standard surgical treatment, they are still prone to recurrence and metastasis [5]. Aberrant transcriptional regulation and epigenetic modification are implicated in genome instability. 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. The clinical value of GI-related lncRNAs (GIlncs) in papillary thyroid cancer (PTC) has not been clarified
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