J Korean Med Sci.  2014 Aug;29(8):1054-1060. 10.3346/jkms.2014.29.8.1054.

Clinicopathological Features of Rare BRAF Mutations in Korean Thyroid Cancer Patients

• Cho U
• Oh WJ
• Bae JS
• Lee S
• Lee YS
• Park GS
• Lee YS
• Jung CK

• KMID: 2129598
• DOI: http://doi.org/10.3346/jkms.2014.29.8.1054

Abstract

The most common BRAF mutation in thyroid cancer is c.1799T>A (p.Val600Glu), and other BRAF mutations are rarely reported. We investigated the clinicopathological features of thyroid cancer with rare BRAF mutations. A total of 2,763 patients with thyroid cancer underwent molecular testing by direct DNA sequencing for mutations in BRAF exon 15. Among them, 2,110 (76.4%) had BRAF mutations. The c.1799T>A mutation was found in 2,093 (76.9%) of 2,722 papillary carcinomas and in one of 7 medullary carcinomas. Sixteen cases (0.76%) harbored rare mutation types. Five cases had single-nucleotide substitutions, 5 cases had small in-frame deletion or insertion, and one harbored a two-nucleotide substitution. Of these mutations, 2 were novel (c.1797_1798insGAGACTACA, c.[1799T>A; 1801_1812del]). The c.1801A>C mutation was identified in 4 follicular variant papillary carcinomas and one follicular carcinoma. None of the patients with the c.1801A>C mutation showed extrathyroidal extension or lymph node metastasis. The prevalence of rare BRAF mutations was 0.76% of all BRAF-positive thyroid cancers, and the rare mutations were associated with less aggressive pathologic features. Although BRAF mutations are detected exclusively in papillary carcinoma, they are also found in medullary carcinoma and follicular carcinoma.

Keyword

Thyroid Neoplasms; BRAF; Mutation; Pathology; Biomarkers

MeSH Terms

Base Sequence
Female
Genetic Markers/genetics
Genetic Predisposition to Disease/epidemiology/*genetics
Humans
Incidence
Male
Middle Aged
Molecular Sequence Data
Mutation/genetics
Polymorphism, Single Nucleotide/genetics
Prevalence
Proto-Oncogene Proteins B-raf/*genetics
Rare Diseases/epidemiology/genetics
Republic of Korea/epidemiology
Risk Factors
Thyroid Neoplasms/epidemiology/*genetics/*pathology
Tumor Markers, Biological/*genetics
Genetic Markers
Proto-Oncogene Proteins B-raf
Tumor Markers, Biological

Figure

• 

  Fig. 1 Electropherograms of case 9 harboring a mutation of c.1797_1798insGAGACTACA. (A) Direct sequencing of BRAF exon 15 PCR product shows 9-bp tail sequence in its electropherograms. (B) Subcloning demonstrates newly inserted nucleotides (GAGACTACA) in between nucleotides positions c.1797 and c.1798.

• 

  Fig. 2 Electropherograms of case 11, harboring a mutation of c.[1799T>A; 1801_1812del]. Direct sequencing shows a complex mutation of c.1799T>A and c.1801_1812del overlapped with the wild-type allele peaks (above). Deletion of 12 nucleotides (*AAATCTCGATGG) and, a substitution at nucleotide position c.1799 are located on the same allele. Subcloning reveals substitution and deletion mutations of the mutant clone, confirming that both mutations are located on the same allele (below).

• 

  Fig. 3 Histological and immunohistochemical aspects of the medullary thyroid carcinoma case (A, B) and electropherogram of its BRAF mutation (C). (A) The tumor shows a characteristic appearance with the presence of round to polygonal tumor cells with fibrosis and amyloid deposition (Hematoxylin and eosin stain, × 200). (B) Calcitonin immunohistochemical stain reveals diffuse and strong positivity in tumor cells (×200). (C) Forward electropherogram show overlapping peak at the nucleotide position c.1799. Mutant peak demonstrates a T to A transversion.

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