Concomitant RAS, RET/PTC, or BRAF mutations in advanced stage of papillary thyroid carcinoma

Minjing Zou, Essa Y Baitei, Ali S Alzahrani, Faisal S BinHumaid, Dania Alkhafaji, Roua A Al-Rijjal, Brian F Meyer, Yufei Shi

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1256-66
Number of pages11
Issue number8
Publication statusPublished - 1 Aug 2014
Externally publishedYes


  • Adolescent
  • Adult
  • Carcinoma/genetics
  • Carcinoma, Papillary
  • Cell Proliferation
  • Cloning, Molecular
  • DNA Mutational Analysis
  • Disease Progression
  • Female
  • Gene Rearrangement
  • Genes, ras/genetics
  • Humans
  • Kaplan-Meier Estimate
  • MAP Kinase Signaling System
  • Male
  • Middle Aged
  • Mutation
  • PAX8 Transcription Factor
  • Paired Box Transcription Factors/genetics
  • Prognosis
  • Proto-Oncogene Proteins B-raf/genetics
  • Proto-Oncogene Proteins c-ret/genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Thyroid Cancer, Papillary
  • Thyroid Neoplasms/genetics
  • Young Adult
  • ras Proteins/genetics


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