Identification of Specific Long Non-Coding RNA Expression: Profile and Analysis of Association with Clinicopathologic Characteristics and BRAF Mutation in Papillary Thyroid Cancer

Background: In recent years, long non-coding RNAs (lncRNAs) have been shown to play a critical regulatory role in cancer biology. However, the contribution of lncRNAs to papillary thyroid cancer (PTC) remains largely unknown. Methods: RNA sequencing and quantitative reverse transcription polymerase chain reaction were used to detect and verify changes to the transcriptome profile in 12 PTC tissues compared to paired normal adjacent tissues. The statistical correlation between differentially expressed lncRNAs and clinicopathologic characteristics was analyzed, and potential lncRNA functions were predicted by examining annotations for the co-expressed mRNAs. Furthermore, the specific subgroup patterns of the PTC transcriptome remodeled by BRAF mutations were also analyzed. Results: A total of 188 lncRNAs and 505 mRNAs were differentially expressed in 50% or more of the PTC tissues (fold change >2; p<0.05) as assessed by RNA-sequencing compared with paired normal adjacent tissues. Forty-seven lncRNAs and 39 mRNAs were verified in 31 pairs of PTC specimens using quantitative reverse transcription polymerase chain reaction, and the results were consistent with the RNA sequencing data. The lncRNAs NONHSAT076747 and NONHSAT122730 were associated with lymph node metastasis, and NONHSAG051968 expression was negatively correlated with tumor size. A co-expression network between differentially expressed lncRNAs and protein-coding RNAs was constructed and analyzed, and functional analysis suggested that the differentially expressed genes mainly participate in ECM-receptor interactions and the focal adhesion pathway. Furthermore, a specific PTC transcriptome subtype pattern stratified by BRAF mutation was also uncovered. The p53 signaling pathway was the most highly enriched pathway among the BRAF mutation-related genes. Conclusions: This study reveals specific changes to the lncRNA profile associated with PTC, and provides new insight into its pathogenesis. The PTC-associated lncRNAs NONHSAG051968, NONHSAT076747, and NONHSAT122730 might be potential diagnostic and therapeutic targets for PTC patients, and lncRNAs with subtype-specific expression stratified by BRAF mutation might be significant in individual molecular subtypes.