Integrative Analysis of Methylation and Transcriptome Identified Epigenetically Regulated lncRNAs With Prognostic Relevance for Thyroid Cancer

Abstract

Emerging evidence has shown that epigenetic changes in DNA methylation, an important regulator of long non-coding RNA (lncRNA) expression, can disturb the expression patterns of lncRNAs and contribute to carcinogenesis. However, knowledge about crosstalk effects between DNA methylation and lncRNA regulation in thyroid cancer (THCA) remain largely unknown. In this study, we performed an integrated analysis of methylation and the transcriptome and identified 483 epigenetically regulated lncRNAs (EpilncRNAs) associated with the development and progression of THCA. These EpilncRNAs can be divided into two categories based on their methylation and expression patterns: 228 HyperLncRNAs and 255 HypoLncRNAs. Then, we identified a methylation-driven 5-lncRNA-based signature (EpiLncPM) to improve prognosis prediction using the random survival forest and multivariate Cox analysis, which were then validated using the training dataset [Hazard ratio (HR) = 50.097, 95% confidence interval (CI): 10.231-245.312, p < 0.001] and testing dataset (HR = 4.395, 95% CI: 0.981-19.686, p = 0.053). Multivariate analysis suggested that the EpiLncPM is an independent prognostic factor. By performing a functional enrichment analysis of GO and KEGG for mRNAs co-expressed with the EpiLncPM, we found that the EpiLncPM was involved in immune and inflammatory-related biological processes. Finally, in situ hybridization analysis in 119 papillary thyroid carcinoma (PTC) tissues and paired adjacent normal tissues revealed that selected candidate lncRNA AC110011 has significantly higher expression of PTC compared to adjacent non-neoplastic tissues, and was closely related to the tumor size, lymph node metastasis, and extrathyroidal extension. In summary, our study characterized the crosstalk between DNA methylation and lncRNA, and provided novel biomarkers for the prognosis of THCA.

Machine Classification of Methylomes in Cancer

“…Additionally, we showed that our gene lists contain many non-coding RNA genes, primarily consisting of lncRNAs, suggesting that methylation alterations at non-coding gene promoters are frequently present in cancer. This fits with the growing body of research showing that lncRNAs and other non-coding RNAs play a key role in cancer [30,31,32].…”

Identification and Analysis of An Epigenetically Regulated Five-lncRNA Signature Associated With Outcome and Chemotherapy Response in Ovarian Cancer

“…These predicted epigenetically regulated lncRNAs in this study would provide an available resource for studying the interplay between lncRNAs and epigenetic regulation. A recent study performed by Li et al (2019) has characterized the crosstalk between DNA methylation and lncRNA expression in thyroid Cancer (THCA) and methylation-driven 5-lncRNA-based signature (EpiLncPM) with potential clinical application in predicting the prognosis of THCA. Therefore, to further investigate whether epigenetically regulated lncRNAs identified here also have potential clinical value, we performed univariate Cox regression analysis with OS and found that only 17 of 419 epigenetically regulated lncRNAs identified here were significantly associated with patients’ outcome.…”

“…Dysregulated lncRNAs have been observed in various cancers and have also been implicated as novel biomarkers in cancer diagnosis, prognosis, and therapeutic response ( Zhou et al, 2016a , 2020 ; Hosseini et al, 2017 ; Huo et al, 2017 ; Tian et al, 2018 ; Bao et al, 2020 ; Sun et al, 2020 ). Previous studies have reported that the expression of some lncRNAs can be regulated by epigenetic modification similar to protein-coding genes ( Zhao et al, 2015 ; Wang et al, 2018 ; Li et al, 2019 ). However, the epigenetically regulated lncRNAs and their association with clinical outcome and therapeutic response in OV remain poorly investigated.…”

Integrative Analysis of DNA Methylation Data and Transcriptome Data Identified a DNA Methylation-Dysregulated Four-LncRNA Signature for Predicting Prognosis in Head and Neck Squamous Cell Carcinoma

“…Recent studies found that aberrant expression of lncRNAs could be caused by altered DNA methylation contributing to carcinogenesis. The relationship between epigenetic alterations and lncRNAs expression has been revealed in several cancers ( Hadji et al, 2016 ; Li et al, 2019 ; Zhang et al, 2019 ; Hou et al, 2020 ; Zhang et al, 2020 ). However, epigenetically dysregulated lncRNAs and their functional and clinical roles in Head and Neck Squamous Cell Carcinoma (HNSCC) are still not explored.…”