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Characterization of a novel complex BRAF mutation in a follicular variant papillary thyroid carcinoma

L Barzon, Dept of Histology, Microbiology and Med Biotechnologies, University of Padova, Padua, I-35121, Italy
G Masi, Dept of Histology, Microbiology and Med Biotechnologies, University of Padova, Padova, Italy
I Merante Boschin, Department of Medical and Surgical Sciences, University of Padova, Padova, Italy
E Lavezzo, Dept of Histology, Microbiology and Med Biotechnologies, University of Padova, Padova, Italy
M Pacenti, Dept of Histology, Microbiology and Med Biotechnologies, University of Padova, Padova, Italy
E Casal Ide, Department of Medical and Surgical Sciences, University of Padova, Padova, Italy
A Toniato, Department of Medical and Surgical Sciences, University of Padova, Padova, Italy
S Toppo, Department of Biological Chemistry, University of Padova, Padova, Italy
G Palu, Dept of Histology, Microbiology and Med Biotechnologies, University of Padova, Padova, Italy
M Pelizzo, Department of Medical and Surgical Sciences, University of Padova, Padova, Italy

Correspondence: Luisa Barzon, Email: luisa.barzon{at}unipd.it

Abstract

Introduction: 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.

Case: 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 to S605 in a stage III, multicentric, follicular variant PTC, occurring in a 50 years-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 B-RAF activity. Although the mutation resulted in loss of a phosphorylation site in the activation loop of B-RAF, it was predicted to increase B-RAF kinase activity by mimiking 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 indicate 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 B-RAF pathway.