title: Concomitant RAS, RET/PTC, or BRAF mutations in advanced stage of papillary thyroid carcinoma.
abstract: BACKGROUND
  RET/PTC rearrangement, RAS, and BRAF mutations are considered to be mutually exclusive in papillary thyroid carcinoma (PTC). However, although concomitant mutations of RET/PTC, RAS, or BRAF have been reported recently, their significance for tumor progression and survival remains unclear. We sought to examine the prognostic value of concomitant mutations in PTC.
  
  
  METHODS
  We investigated 88 PTC for concomitant mutations. Mutation in BRAF exon 15, KRAS, NRAS, and HRAS were studied by polymerase chain reaction (PCR)-sequencing of tumor DNA; RET/PTC rearrangement was determined by reverse transcription (RT)-PCR-sequencing of tumor cDNA.
  
  
  RESULTS
  BRAF(V600E) was detected in 39 of 82 classic PTC (CPTC) and in all three tall-cell variants (49%, 42/85). KRAS mutation (p.Q61R and p.S65N) was detected in two CPTC (2%, 2/88) and NRAS(Q61R) in one CPTC and two follicular variant PTC (FVPTC; 3%, 3/88). KRAS(S65N) was identified for the first time in thyroid cancer and could activate mitogen-associated protein kinase (MAPK). RET/PTC-1 was detected in nine CPTC, one tall-cell variant, and two FVPTC. Concomitant BRAF(V600E) and KRAS, or BRAF(V600E) and RET/PTC-1 mutations were found in two CPTC, and six CPTC and one tall-cell variant, respectively. In total, 11 concomitant mutations were found in 88 PTC samples (13%), and most of them were in the advanced stage of disease (8/11, 73%; p<0.01).
  
  
  CONCLUSIONS
  Our data show that concomitant mutations are a frequent event in advanced PTC and are associated with poor prognosis. The concomitant mutations may represent intratumor heterogeneity and could exert a gene dosage effect to promote disease progression. KRAS(S65N) can constitutively activate the MAPK pathway.
authors.affiliation: 1 Department of Genetics, King Faisal Specialist Hospital and Research Centre , Riyadh, Saudi Arabia .
authors.forename: Minjing
authors.initials: M
authors.lastname: Zou
authors.forename: Essa Y
authors.initials: EY
authors.lastname: Baitei
authors.forename: Ali S
authors.initials: AS
authors.lastname: Alzahrani
authors.forename: Faisal S
authors.initials: FS
authors.lastname: BinHumaid
authors.forename: Dania
authors.initials: D
authors.lastname: Alkhafaji
authors.forename: Roua A
authors.initials: RA
authors.lastname: Al-Rijjal
authors.forename: Brian F
authors.initials: BF
authors.lastname: Meyer
authors.forename: Yufei
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000293:Adolescent; D000328:Adult; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D002291:Carcinoma, Papillary; D049109:Cell Proliferation; D003001:Cloning, Molecular; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D015321:Gene Rearrangement; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D053208:Kaplan-Meier Estimate; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000072636:PAX8 Transcription Factor; C083325:PAX8 protein, human; D051761:Paired Box Transcription Factors; D051096:Proto-Oncogene Proteins c-ret; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D018631:ras Proteins