Global RNA Expression and DNA Methylation Patterns in Primary Anaplastic Thyroid Cancer

Abstract

Anaplastic thyroid cancer (ATC) is one of the most malignant tumors, with a median survival of only a few months. The tumorigenic processes of this disease have not yet been completely unraveled. Here, we report an mRNA expression and DNA methylation analysis of fourteen primary ATCs. ATCs clustered separately from normal thyroid tissue in unsupervised analyses, both by RNA expression and by DNA methylation. In expression analysis, enrichment of cell-cycle-related genes as well as downregulation of genes related to thyroid function were seen. Furthermore, ATC displayed a global hypomethylation of the genome but with hypermethylation of CpG islands. Notably, several cancer-related genes displayed a correlation between RNA expression and DNA methylation status, including MTOR, NOTCH1, and MAGI1. Furthermore, TSHR and SLC26A7, encoding the thyroid-stimulating hormone receptor and an iodine receptor highly expressed in normal thyroid, respectively, displayed low expression as well as aberrant gene body DNA methylation. This study is the largest investigation of global DNA methylation in ATC to date. It shows that aberrant DNA methylation is common in ATC and likely contributes to tumorigenesis in this disease. Future explorations of novel treatments should take this into consideration.Cancers 2020, 12, 680 2 of 11 to display promoter hypermethylation in ATC include PTEN, RAP1GAP, RASAL1, REC8, RASSF1,, whereas hypomethylation has been observed in NOTCH4, MAP17, and TCL1B. Notably, TSHR and NKX2-1 (previously TTF-1), involved in thyroid functions, have also been reported to be hypermethylated in ATC [17,18].Matched expression and methylation data may unravel genes that are dysregulated by methylation and that could contribute to tumorigenesis. However, no such studies have hitherto been performed on the genomic level in ATC. Here, we applied RNA sequencing (RNA-seq) and genome-wide methylation arrays, including 850,000 CpG sites, on primary ATC tumor samples to identify novel genes that exhibit significant methylation and expression correlation and to further delineate the tumorigenic process of ATC.

Alterations in SLC4A2, SLC26A7 and SLC26A9 Drive Acid–Base Imbalance in Gastric Neuroendocrine Tumors and Uncover a Novel Mechanism for a Co-Occurring Polyautoimmune Scenario

“…Cotransporter genes involved in achlorhydria (SLC26A7, SLC26A9 and ATP4A) were also strongly associated with thyroid disease in thyrogastric patients, suggesting a monogenic model for the thyrogastric syndrome ( Table 3 ). Remarkably, SLC26A7 was found to be expressed in both gastric and thyroid tissues ( Figure S4 ) and recently, alterations in SLC26A7 were reported associated with in thyroid diseases, such thyroid dyshormonogenesis [ 26 ], congenital goitrous hypothyroidism [ 27 ] and primary anaplastic thyroid cancer [ 28 ]. Similarly, variants in other thyroid-only expressed genes involved in the acid–base balance (not included in our panel) might compose a digenic scenario together with genes expressed in PCs.…”

Computational methods for the prediction of chromatin interaction and organization using sequence and epigenomic profiles

“…Ravi et al . [ 92 ] performed an mRNA expression and DNA methylation analysis of anaplastic thyroid cancer with ELMER v.2 [ 35 ], showing that aberrant DNA methylation affects gene expression and likely contributes to tumorigenesis in this disease. Besides, Naville et al .…”

MAGI1, a Scaffold Protein with Tumor Suppressive and Vascular Functions

“…Regarding MAGI1, a recent report revealed that MAGI1 mediates tumor metastasis through the c-Myb/miR-520h/MAGI1 signaling pathway in renal cell carcinoma [125]. Somatic genomic alterations of MAGI1 genes were also found to be associated with metachronous gastric cancer development [126], and in a DNA methylation analysis of anaplastic thyroid cancer (ATC), MAGI1 displayed promoter methylation as well as decreased expression in ATC compared with normal thyroid tissue [127]. Aberrant DNA methylation can result in both upregulation of oncogenes and the silencing of tumor suppressor genes [128].…”