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Epigenetic Alterations and Canonical Pathway Disruption in Papillary Thyroid Cancer: A Genome-wide Methylation
Michael G White1, Sapna Nagar1, Briseis Aschebrook-Kilfoy2
1Endocrine Surgery Research Program, Department of Surgery, The University of Chicago, Chicago, IL, USA.
Background:
Alterations in DNA methylation have been demonstrated in a variety of malignancies, including papillary thyroid cancer (PTC). The full extent of dysregulation in PTC and the downstream affected pathways remains unclear. Here we report a genome-wide analysis of PTC methylation, the dysregulation of various canonical pathways, and assess its potential as a diagnostic test.
Methods:
A discovery set utilized 49 PTCs and matched normal controls from The Cancer Genome Atlas. Another set of 16 PTCs and 13 normal controls were used as a replication set. Genome-wide methylation analysis was done using Illumina 450 K methylation chips. Differentially methylated loci (DML) were identified by comparing PTC and matched normal tissues. DML were defined as false-discovery rate p < 0.05 and absolute Δβ ≥ 0.2. DML were then analyzed for pathway and disease commonalities using Qiagen Ingenuity Pathway Analysis.
Results:
Of 485,577 CpG sites analyzed, 1226 DML were identified in our discovery and replication sets, and 1061 (86.5 %) DML showed hypomethylation when comparing tumor with normal tissue. Support vector machine classification was able to differentiate benign from malignant tissue in 107 (94.7 %) of 113 tested samples, including 15 (83.3 %) of 18 samples lacking a clearly deleterious mutation. Statistically significant associations with multiple canonical pathways, diseases, and biofunctions were observed including PI3K, PTEN, wnt/β-catenin, and p53.
Conclusions:
Epigenetic dysregulation of multiple canonical pathways are associated with the development of PTC. This methylation signature shows promise as a future adjunctive screening test for thyroid nodules.
Insights
Altered DNA methylation patterns are common in papillary thyroid cancer (PTC). This study identifies key methylation changes and suggests their potential as a diagnostic tool for thyroid nodules.
Area of Science:
- Genomic Medicine
- Epigenetics
- Oncology
Background:
- DNA methylation alterations are observed in various cancers, including papillary thyroid cancer (PTC).
- The complete spectrum of epigenetic dysregulation in PTC and its impact on cellular pathways are not fully understood.
- This study investigates genome-wide DNA methylation patterns in PTC to elucidate affected pathways and diagnostic potential.
Purpose of the Study:
- To perform a genome-wide methylation analysis in papillary thyroid cancer (PTC).
- To identify differentially methylated loci (DML) and associated canonical pathways.
- To evaluate the potential of DNA methylation signatures as a diagnostic biomarker for PTC.
Main Methods:
- Genome-wide methylation analysis using Illumina 450K chips on PTC and matched normal tissues from The Cancer Genome Atlas and a replication set.
- Identification of differentially methylated loci (DML) with a false-discovery rate p < 0.05 and absolute Δβ ≥ 0.2.
- Pathway and disease association analysis using Qiagen Ingenuity Pathway Analysis.
Main Results:
- 1226 DML were identified across discovery and replication sets, with 86.5% showing hypomethylation in tumor tissue.
- Support vector machine classification distinguished benign from malignant tissue in 94.7% of samples.
- Significant associations were found with canonical pathways including PI3K, PTEN, wnt/β-catenin, and p53.
Conclusions:
- Epigenetic dysregulation, specifically DNA methylation changes in key pathways, is linked to PTC development.
- The identified methylation signature demonstrates promise as an adjunctive screening tool for thyroid nodules.
- Further validation is warranted to establish its clinical utility in diagnosing PTC.
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