title: RAS mutations in indeterminate thyroid nodules are predictive of the follicular variant of papillary thyroid carcinoma.
abstract: OBJECTIVE
  RAS mutations are the most common mutations in thyroid nodules with indeterminate cytology by fine-needle aspiration cytology (FNAC), and are mutually exclusive with BRAF mutations. However, the diagnostic utility of RAS mutation analysis is uncertain. We evaluated the diagnostic utility of RAS mutation analysis in indeterminate thyroid nodules.
  A total of 155 thyroid nodules (90 benign and 65 indeterminate) negative for BRAF(V) (600E) mutations on FNAC were analysed for mutations in RAS codon 61 using pyrosequencing methods. We evaluated diagnostic accuracy of RAS mutation for predicting thyroid malignancy based on the surgical pathologic diagnosis.
  
  
  RESULTS
  Among the 65 BRAF(V) (600E) -negative indeterminate thyroid nodules identified by FNAC, 25 (38·5%) exhibited point mutations in RAS 61 consisting of 18 NRAS 61 (72%), and 7 HRAS 61 (28%) mutations. In contrast, only five of 90 (5·6%) nodules with benign cytology had RAS mutations. Only two of 25 (8·0%) RAS 61(+) indeterminate nodules exhibited malignant ultrasonographic features. Of the 15 patients with RAS 61(+) -indeterminate nodules who underwent thyroid surgery, 14 (93·3%) were diagnosed as malignant, including 13 follicular variant of papillary thyroid carcinomas (FVPTC), and one follicular thyroid carcinoma (FTC). The average tumour size was 1·79 ± 0·62 cm. Multifocality was seen in 28·6% of cases, with 7·1% exhibiting extrathyroidal extension; no lymph node or distant metastases were evident. Based on the surgical pathologic diagnosis results, preoperative RAS 61 mutation analysis on FNAC exhibited 93·3% sensitivity, 75·0% specificity, 93·3% positive predictive value, 75·0% negative predictive value and 89·5% diagnostic accuracy for predicting malignancies.
  
  
  CONCLUSIONS
  Our results suggest that RAS mutation analysis holds great promise as a preoperative diagnostic tool for predicting FVPTC in cytologically and sonographically indeterminate nodules negative for BRAF mutations.
authors.affiliation: Department of Internal Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea; Department of Internal Medicine, Korea University Hospital, Korea University College of Medicine, Seoul, Korea.
authors.forename: Jee Hyun
authors.initials: JH
authors.lastname: An
authors.forename: Kee-Ho
authors.initials: KH
authors.lastname: Song
authors.forename: Suk Kyeong
authors.initials: SK
authors.lastname: Kim
authors.forename: Kyoung Sik
authors.initials: KS
authors.lastname: Park
authors.forename: Young Bum
authors.initials: YB
authors.lastname: Yoo
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Yang
authors.forename: Tae Sook
authors.initials: TS
authors.lastname: Hwang
authors.forename: Dong-Lim
authors.initials: DL
authors.lastname: Kim
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000000981:diagnostic imaging / Q000235:genetics*; D000328:Adult; D000368:Aged; D044963:Biopsy, Fine-Needle; D002277:Carcinoma / Q000000981:diagnostic imaging / Q000235:genetics*; D002291:Carcinoma, Papillary; D004252:DNA Mutational Analysis; D005260:Female; D011905:Genes, ras; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017354:Point Mutation; D011237:Predictive Value of Tests; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics*; D016606:Thyroid Nodule / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology*; D014463:Ultrasonography; D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins