Prognostic Classifier Based on Genome-Wide DNA Methylation Profiling in Well-Differentiated Thyroid Tumors

Abstract

Context:Even though the majority of well-differentiated thyroid carcinoma (WDTC) is indolent, a number of cases display an aggressive behavior. Cumulative evidence suggests that the deregulation of DNA methylation has the potential to point out molecular markers associated with worse prognosis.Objective:To identify a prognostic epigenetic signature in thyroid cancer.Design:Genome-wide DNA methylation assays (450k platform, Illumina) were performed in a cohort of 50 nonneoplastic thyroid tissues (NTs), 17 benign thyroid lesions (BTLs), and 74 thyroid carcinomas (60 papillary, 8 follicular, 2 Hürthle cell, 1 poorly differentiated, and 3 anaplastic). A prognostic classifier for WDTC was developed via diagonal linear discriminant analysis. The results were compared with The Cancer Genome Atlas (TCGA) database.Results:A specific epigenetic profile was detected according to each histological subtype. BTLs and follicular carcinomas showed a greater number of methylated CpG in comparison with NTs, whereas hypomethylation was predominant in papillary and undifferentiated carcinomas. A prognostic classifier based on 21 DNA methylation probes was able to predict poor outcome in patients with WDTC (sensitivity 63%, specificity 92% for internal data; sensitivity 64%, specificity 88% for TCGA data). High-risk score based on the classifier was considered an independent factor of poor outcome (Cox regression, P < 0.001).Conclusions:The methylation profile of thyroid lesions exhibited a specific signature according to the histological subtype. A meaningful algorithm composed of 21 probes was capable of predicting the recurrence in WDTC.

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

“…ATC clustered separately from normal thyroid tissue both by expression and by methylation ( Figures 1 and 2), in line with previous studies [4,7,10,11] and showing that the tumor cell percentage was relatively high in the tumor samples. The expression signature of ATC was dominated by cell-cycle-related processes (Table S2), reflecting the high proliferative rate of this malignancy.…”

“…The expression signature of ATC was dominated by cell-cycle-related processes (Table S2), reflecting the high proliferative rate of this malignancy. In regards to DNA methylation, the majority of differentially methylated CpGs in ATC were hypomethylated and in intergenic regions (Figure 2), in line with previous studies [10,11,24]. Global hypomethylation is a common phenomenon in cancer and is believed to be associated with genomic instability [25], agreeing well with the genomic complexity generally seen in ATC [20].…”

“…Similarly, all DNA methylation studies done so far on ATC have been performed on very small cohorts of samples. Two have included genome-wide methylation analyses using arrays, each including only two or three ATC cases each [10,11]. Putative tumor suppressor genes that have been reported…”

Association between DNA methylation profile and malignancy in follicular-patterned thyroid neoplasms

“…By using 450K arrays, Bisarro dos Reis confirmed that while DNA hypomethylation was predominant in PTC, hypermethylation was present in FTC and benign thyroid lesions. However, benign lesions showed significantly less numerous differentially methylated CpGs (222 hypomethylated and 1531 hypermethylated) with respect to FTC (1475 hypomethylated and 4100 hypermethylated) (Bisarro Dos Reis et al 2017). Importantly, the same study also suggested prognostic implications of the DNA methylation profile, with massive hypomethylation in aggressive (PDTC/ATC) thyroid cancer subtypes (Bisarro Dos Reis et al 2017).…”

“…However, benign lesions showed significantly less numerous differentially methylated CpGs (222 hypomethylated and 1531 hypermethylated) with respect to FTC (1475 hypomethylated and 4100 hypermethylated) (Bisarro Dos Reis et al 2017). Importantly, the same study also suggested prognostic implications of the DNA methylation profile, with massive hypomethylation in aggressive (PDTC/ATC) thyroid cancer subtypes (Bisarro Dos Reis et al 2017). Recently, Yim et al (2019) showed that a DNA methylation-based molecular method, named Diagnostic DNA Methylation Signature approach (DDMS), features high sensitivity/specificity in the identification of malignant and benign thyroid nodules.…”