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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 - J. Korean Med. Sci. (2014)

Bottom Line: The c.1799T>A mutation was found in 2,093 (76.9%) of 2,722 papillary carcinomas and in one of 7 medullary carcinomas.None of the patients with the c.1801A>G mutation showed extrathyroidal extension or lymph node metastasis.Although BRAF mutations are detected exclusively in papillary carcinoma, they are also found in medullary carcinoma and follicular carcinoma. [Corrected]

View Article: PubMed Central - PubMed

Affiliation: Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea.

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>G mutation was identified in 4 follicular variant papillary carcinomas and one follicular carcinoma. None of the patients with the c.1801A>G 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. [Corrected]

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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.
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Figure 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.

Mentions: We previously reported 3 novel complex mutations (cases 13, 14 and 15) and additionally found 2 novel BRAF mutations, c.1797_1798insGAGACTACA and c.[ 1799T>A; 1801_1812del] (case 9 and case 11, respectively). Sequence analysis of case 9 showed 9-nucleotide GAGACTACA insertion between positions c.1797 and c.1798 (c.1797_1798insGAGACTACA). This mutation leads to the insertion of 3 amino acids, glutamate-threonine-threonine, between codons 599 and 600 (p.Thr599_Val600insGluThrThr) (Fig. 1). The mutation in case 11 consisted of the usual T to A substitution at position c.1799 (c.1799T>A), followed by deletion of 12 nucleotides from c.1801 to c.1812. These mutations lead to a substitution from valine to glutamate at codon 600 and in-frame deletion of 4 amino acids from codons 601 to 604 (p.[(Val600Glu; Lys601_Trp604del)]) (Fig. 2). Cloning and subsequent sequence analysis of the PCR amplicon demonstrated that both mutations were located within the same allele.


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 - J. Korean Med. Sci. (2014)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4129195&req=5

Figure 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.
Mentions: We previously reported 3 novel complex mutations (cases 13, 14 and 15) and additionally found 2 novel BRAF mutations, c.1797_1798insGAGACTACA and c.[ 1799T>A; 1801_1812del] (case 9 and case 11, respectively). Sequence analysis of case 9 showed 9-nucleotide GAGACTACA insertion between positions c.1797 and c.1798 (c.1797_1798insGAGACTACA). This mutation leads to the insertion of 3 amino acids, glutamate-threonine-threonine, between codons 599 and 600 (p.Thr599_Val600insGluThrThr) (Fig. 1). The mutation in case 11 consisted of the usual T to A substitution at position c.1799 (c.1799T>A), followed by deletion of 12 nucleotides from c.1801 to c.1812. These mutations lead to a substitution from valine to glutamate at codon 600 and in-frame deletion of 4 amino acids from codons 601 to 604 (p.[(Val600Glu; Lys601_Trp604del)]) (Fig. 2). Cloning and subsequent sequence analysis of the PCR amplicon demonstrated that both mutations were located within the same allele.

Bottom Line: The c.1799T>A mutation was found in 2,093 (76.9%) of 2,722 papillary carcinomas and in one of 7 medullary carcinomas.None of the patients with the c.1801A>G mutation showed extrathyroidal extension or lymph node metastasis.Although BRAF mutations are detected exclusively in papillary carcinoma, they are also found in medullary carcinoma and follicular carcinoma. [Corrected]

View Article: PubMed Central - PubMed

Affiliation: Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea.

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>G mutation was identified in 4 follicular variant papillary carcinomas and one follicular carcinoma. None of the patients with the c.1801A>G 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. [Corrected]

Show MeSH
Related in: MedlinePlus