title: Characterization of a novel complex BRAF mutation in a follicular variant papillary thyroid carcinoma.
abstract: BACKGROUND
  Activating mutations of the BRAF oncogene are frequently detected in papillary thyroid carcinoma (PTC) and have been associated with a worse prognosis. The amino acid substitution V600E accounts for 90% of all oncogenic BRAF mutations and is typically detected in classic PTCs, whereas other less frequent BRAF mutations seem to be associated with other PTC histotypes.
  
  
  METHODS
  Screening for activating BRAF mutations in a series of 83 PTCs identified the most common V600E mutation in 39 cases (histologically, 38 classic PTCs and 1 sclerosing variant PTC) and a complex in-frame mutation involving amino acids V600-S605 in a stage III multicentric follicular variant PTC, occurring in a 50-year-old female patient, who was affected by hypothyroidism in autoimmune thyroiditis and had a family history of PTC and autoimmune thyroiditis. Since the identified BRAF mutation was novel in the literature, bioinformatic modeling was performed to predict its impact on BRAF activity. Although the mutation resulted in loss of a phosphorylation site in the activation loop of BRAF, it was predicted to increase BRAF kinase activity by mimicking an activating phosphorylation.
  
  
  CONCLUSIONS
  This study, which reports a new BRAF mutation, highlights the usefulness of bioinformatic modeling in the prediction of functional effects of new mutations and indicates that mutation-specific screening tests might miss some rare BRAF mutations. These facts should be taken into consideration in the molecular diagnosis of thyroid cancer and in the design of therapeutic protocols based on inhibitors of the BRAF pathway.
authors.affiliation: Department of Histology, Microbiology, and Medical Biotechnologies, University of Padova, I-35121 Padova, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Barzon
authors.forename: Giulia
authors.initials: G
authors.lastname: Masi
authors.forename: Isabella Merante
authors.initials: IM
authors.lastname: Boschin
authors.forename: Enrico
authors.initials: E
authors.lastname: Lavezzo
authors.forename: Monia
authors.initials: M
authors.lastname: Pacenti
authors.forename: Eric
authors.initials: E
authors.lastname: Casal Ide
authors.forename: Antonio
authors.initials: A
authors.lastname: Toniato
authors.forename: Stefano
authors.initials: S
authors.lastname: Toppo
authors.forename: Giorgio
authors.initials: G
authors.lastname: Palù
authors.forename: Maria Rosa
authors.initials: MR
authors.lastname: Pelizzo
mesh_terms: D000595:Amino Acid Sequence; D018265:Carcinoma, Papillary, Follicular / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D017433:Protein Structure, Secondary; D048493:Proto-Oncogene Proteins B-raf / Q000737:chemistry / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics*
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf