title: Role of BRAF and RAS Mutations in Extrathyroidal Extension in Papillary Thyroid Cancer.
abstract: OBJECTIVE
  Extrathyroidal extension (ETE) indicates the invasiveness of primary thyroid tumor into the adjacent tissue, and its importance as a prognostic factor overrides tumor size in classifying the cancer stage. The aim of this study was to determine the molecular basis of ETE in papillary thyroid carcinomas (PTCs).
  
  
  METHODS
  We systematically defined genes and pathways regulated in ETE using mutation and gene expression profiles from The Cancer Genome Atlas, and examined the effect of BRAF and RAS mutations on ETE. The significance of these genes was further validated using public microarray data.
  
  
  RESULTS
  Genes related to extracellular matrix and immune response were significantly up-regulated in ETE and ion-transport genes were often down-regulated. Differentiation properties and WNT signaling were also found to be altered by ETE. BRAF and RAS mutations were shown to have distinct effects on genes associated with ETE. Specifically, PAX8 and its downstream target WNT4 were differentially expressed according to mutation status in addition to ETE, indicating their critical roles in cell motility.
  
  
  CONCLUSIONS
  BRAF V600E mutation predisposes PTC cells toward invasive phenotypes, while RAS mutation confers resistance to ETE. The differential regulation appears to be mediated through WNT4.
authors.affiliation: Seoul National University Biomedical Informatics, Division of Biomedical Informatics, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Ji Yeon
authors.initials: JY
authors.lastname: Park
authors.affiliation: Department of Surgery, Seoul National University Hospital and College of Medicine, Seoul, Republic of Korea Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jin Wook
authors.initials: JW
authors.lastname: Yi
authors.affiliation: Seoul National University Biomedical Informatics, Division of Biomedical Informatics, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Chan Hee
authors.initials: CH
authors.lastname: Park
authors.affiliation: Seoul National University Biomedical Informatics, Division of Biomedical Informatics, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Younggyun
authors.initials: Y
authors.lastname: Lim
authors.affiliation: Seoul National University Biomedical Informatics, Division of Biomedical Informatics, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Kye Hwa
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Department of Surgery, Seoul National University Hospital and College of Medicine, Seoul, Republic of Korea Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Kyu Eun
authors.initials: KE
authors.lastname: Lee
authors.affiliation: Seoul National University Biomedical Informatics, Division of Biomedical Informatics, Seoul National University College of Medicine, Seoul, Republic of Korea juhan@snu.ac.kr.
authors.forename: Ju Han
authors.initials: JH
authors.lastname: Kim
mesh_terms: D002277:Carcinoma / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002291:Carcinoma, Papillary; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D011905:Genes, ras; D006801:Humans; D017136:Ion Transport / Q000235:genetics; D009154:Mutation; D009361:Neoplasm Invasiveness; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D059016:Tumor Microenvironment / Q000235:genetics; D060449:Wnt Signaling Pathway
chemical_list: D014157:Transcription Factors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF; Papillary thyroid cancer; RAS; WNT signaling; extrathyroidal extension