title: Epigenetic Alterations and Canonical Pathway Disruption in Papillary Thyroid Cancer: A Genome-wide Methylation Analysis.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Endocrine Surgery Research Program, Department of Surgery, The University of Chicago, Chicago, IL, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: White
authors.affiliation: Endocrine Surgery Research Program, Department of Surgery, The University of Chicago, Chicago, IL, USA.
authors.forename: Sapna
authors.initials: S
authors.lastname: Nagar
authors.affiliation: Department of Public Health Sciences, The University of Chicago, Chicago, IL, USA.
authors.forename: Briseis
authors.initials: B
authors.lastname: Aschebrook-Kilfoy
authors.affiliation: Department of Public Health Sciences, The University of Chicago, Chicago, IL, USA.
authors.forename: Farzana
authors.initials: F
authors.lastname: Jasmine
authors.affiliation: Department of Public Health Sciences, The University of Chicago, Chicago, IL, USA.
authors.forename: Muhammad G
authors.initials: MG
authors.lastname: Kibriya
authors.affiliation: Department of Public Health Sciences, The University of Chicago, Chicago, IL, USA.
authors.forename: Habibul
authors.initials: H
authors.lastname: Ahsan
authors.affiliation: Endocrine Surgery Research Program, Department of Surgery, The University of Chicago, Chicago, IL, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Angelos
authors.affiliation: Endocrine Surgery Research Program, Department of Surgery, The University of Chicago, Chicago, IL, USA.
authors.forename: Edwin L
authors.initials: EL
authors.lastname: Kaplan
authors.affiliation: Endocrine Surgery Research Program, Department of Surgery, The University of Chicago, Chicago, IL, USA. rgrogan@surgery.bsd.uchicago.edu.
authors.forename: Raymon H
authors.initials: RH
authors.lastname: Grogan
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor / Q000235:genetics*; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D018899:CpG Islands; D019175:DNA Methylation; D057890:Epigenomics; D005260:Female; D005500:Follow-Up Studies; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D015996:Survival Rate; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor