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15.03.2016 | Endocrine Tumors | Ausgabe 7/2016

Annals of Surgical Oncology 7/2016

Epigenetic Alterations and Canonical Pathway Disruption in Papillary Thyroid Cancer: A Genome-wide Methylation Analysis

Zeitschrift:
Annals of Surgical Oncology > Ausgabe 7/2016
Autoren:
MD Michael G. White, MD Sapna Nagar, PhD Briseis Aschebrook-Kilfoy, MD, PhD Farzana Jasmine, MD, PhD Muhammad G. Kibriya, MD, MMedSC Habibul Ahsan, MD, PhD Peter Angelos, MD Edwin L. Kaplan, MD Raymon H. Grogan
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1245/​s10434-016-5185-4) contains supplementary material, which is available to authorized users.

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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Zusatzmaterial
Supplementary material 1 (DOCX 482 kb)
10434_2016_5185_MOESM1_ESM.docx
Supplementary material 2 (DOCX 490 kb)
10434_2016_5185_MOESM2_ESM.docx
Supplementary material 3 (DOCX 528 kb)
10434_2016_5185_MOESM3_ESM.docx
Literatur
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