Abstract
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.
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Acknowledgment
R.H.G. was supported by award K12CA139160 from the National Cancer Institute (NCI). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NCI or the U.S. National Institutes of Health. We thank Dr. Larissa Furtado for her assistance and expertise in characterizing the somatic mutation profiles of these samples. We thank Dr. Nicole Cipriani for her assistance and expertise in endocrine pathology evaluations. The authors used data generated by TCGA managed by the NCI and National Human Genome Research Institute; information about TCGA can be found online at http://cancergenome.nih.gov.
Disclosure
Michael G. White, Sapna Nagar, Briseis Aschebrook-Kilfoy, Farzana Jasmine, Muhammad G. Kibriya, Habibul Ahsan, Peter Angelos, Edwin L. Kaplan, and Raymon H. Grogan declare no conflict of interest.
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White, M.G., Nagar, S., Aschebrook-Kilfoy, B. et al. Epigenetic Alterations and Canonical Pathway Disruption in Papillary Thyroid Cancer: A Genome-wide Methylation Analysis. Ann Surg Oncol 23, 2302–2309 (2016). https://doi.org/10.1245/s10434-016-5185-4
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DOI: https://doi.org/10.1245/s10434-016-5185-4