Korean J Endocr Surg.  2010 Sep;10(3):147-151. 10.16956/kjes.2010.10.3.147.

Relationship between BRAF Mutations in Papillary Thyroid Carcinomas and Clinicopathologic Factors

• Kim JH
• Choi JY

• KMID: 2375716
• DOI: http://doi.org/10.16956/kjes.2010.10.3.147

Abstract

PURPOSE
Papillary thyroid carcinomas (PTCs) account for about 80% of all thyroid cancers. B-Raf proto-oncogene serine/threonine-protein kinase (BRAF) transversion mutation T1796A is present in 29~69% of PTCs, and is a potential prognostic marker for PTC as it may be associated with aggressive tumors. This study investigated the prevalence of BRAF exon 15 T1796A in thyroid tissues obtained by a thyroidectomy, and correlation of the mutation with clinicopathological factors.
METHODS
One hundred nine PTC patients as determined histologically by thyroidectomy between January 2007 and June 2009 were evaluated to detect T1796A in intraoperative fresh tissue. The mutation was sought in all specimens using DNA sequencing.
RESULTS
The mean patient age at surgery was 45.1 years and tumors had a median tumor diameter of 11.4 mm. At the time of diagnosis, 28 of the 109 patients presented with some kind of extrathyroideal invasion of the tumor, and 48 had lymph node metastases. Sixty two patients were stages 1 or 2. There was no distant metastasis, A missense mutation was found at T1796A in exon 15 in 35 of the 109 (32%) PTCs. In patients with conventional papillary thyroid cancer, the BRAF(V600E) mutation was significantly associated with lymph node metastasis (P=0.024), high TNM stage (1 and 2 vs. 3 and 4, P=0.022), tumor size (P=0.01) and capsular invasion (P=0.033).
CONCLUSION
The BRAF(V600E) mutation is a poor prognostic factor independent from other clinicopathological features.

Keyword

Papillary thyroid carcinoma; BRAF(V600E)

MeSH Terms

Diagnosis
Exons
Humans
Lymph Nodes
Mutation, Missense
Neoplasm Metastasis
Phosphotransferases
Prevalence
Proto-Oncogenes
Sequence Analysis, DNA
Thyroid Gland*
Thyroid Neoplasms*
Thyroidectomy
Phosphotransferases

Figure

• 

  Fig. 1. T1799A in papillary thyroid carcinoma.

Reference

1.Grebe SK., Hay ID. Follicular cell-derived thyroid carcinomas. Cancer Treat Res. 1997. 89:91.

2.Ruegemer JJ., Hay ID., Bergstralh EJ., Ryan JJ., Offord KP., Gorman CA. Distant metastases in differentiated thyroid carcinoma: a multivariate analysis of prognostic variables. J Clin Endocrinol Metab. 1988. 67:501–8.

3.Hamacher C., Studer H., Zbaeren J., Schatz H., Derwahl M. Expression of functional stimulatory guanine nucleotide binding protein in nonfunctioning thyroid adenomas is not correlated to adenylate cyclase activity and growth of these tumors. J Clin Endocrinol Metab. 1995. 80:1724–32.

4.Fusco A., Grieco M., Santoro M., Berlingieri MT., Pilotti S., Pierotti MA, et al. A new oncogene in human thyroid papillary carcinomas and their lymphnodal metastases. Nature. 1987. 328:170–2.

5.Feinstein E., Gale RP., Reed J., Canaani E. Expression of the normal p53 gene induces differentiation of K562 cells. Oncogene. 1992. 7:1853–7.

6.Fusco A., Viglietto G., Saantoro M. A new mechanism of BRAF activation in human thyroid papillary carcinomas. J Clin Inves. 2005. 115:20–3.

7.Frasca F., Nucera C., Pellegriti G., Gangemi P., Attard M., Stella M, et al. BRAFV600E mutation and the biology of papillary thyroid cancer. Endo related cancer. 2008. 15:191–205.

8.Kebebew E., Weng J., Bauer J., Ranvier G., Clark OH., Duh QY, et al. The prevalence and prognostic value of BRAF mutation in thyroid cancer. Ann Surg. 2007. 246:466–71.

9.Elisei R., Ugolini C., Viola D., Lupi C., Biagini A., Giannini R, et al. BRAF^V600E mutation and outcome of patients with papillary thyroid carcinoma: a 15-year median follow-up study. J Clin Endocrinol Metab. 2008. 93:3943–9.

10.Cohen Y., Xing M., Mambo E., Guo Z., Wu G., Trink B, et al. BRAF mutation in papillary thyroid carcinoma. J National Cancer Institute. 2003. 95:625–7.

11.Davies H., Bignell GR., Cox C., Stehens P., Edkins S., Clegg S. Mutations of the BRAF gene in human cancer. Nature (Lond.). 2002. 417:949–54.

12.Sanders LE., Cady B. Differentiated thyroid cancer. Reexa-minationo f risk groups and outcome of treatment. Arch Surg. 1998. 133:419–25.

13.Haigh P., Urbach DR., Rotstein LE. AMES prognostic index and extent of thyroidectomy for well differentiated thyroid cancer in the united states. Surgery. 2004. 136:609–16.

14.Hay ID., Thompson GB., Grant CS., Bergstralh EJ., Dvorak CE., Gorman CA. Papillary thyroid carcinoma managed at the mayo clinic during six decades (1940∼1999): temporal trends in initial theraphy and long-term outcome in 2,444 consecutively treated patients. World J Surg. 2002. 26:879–85.

15.Kimura ET., Nikiforova MN., Zhu Z., Knauf JA., Nikiforv YE., Fagin JA. High prevalence of BRAF mutation in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res. 2003. 63:1454–7.

16.Cohen Y., Xing M., Mambo E., Guo Z., Wu Z., Trink B, et al. BRAF mutation in papillary thyroid carcinoma. J Natl Cancer Inst. 2003. 95:625–7.

17.Soares P., Trovisco V., Rhosa AS., Lima J., Castro P., Preto A, et al. BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC. Oncogene. 2003. 22:4578–80.

18.Xu X., Quiros RM., Gattusso P., Ain KB., Prinz RA. High prevalence of BRAF gene mutation in papillary thyroid carcinomas and thyroid tumor cell lines. Cancer Res. 2003. 63:4561–7.

19.Rha SY., Lee JC., Kwon KH., Lee HJ., Kim KS., Jo YS, et al. The relationship between the BRAF mutations in thyroid papillary carcinomas and the prognostic factors. J Korean Endoclinol. 2005. 20:224–9.

20.Puxeddu E., Moretti S., Elisei R., Romei C., Pascucci R., Martinelli M, et al. BRAF (V599E) mutation is the leading genetic event in adult sporadic papillary thyroid carcinomas. J Clin Endocrinol Metab. 2004. 89:2414–20.

21.Xing M., Westra WH., Tufano RP., Cohen Y., Rosenbaum E., Rhoden KJ, et al. BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab. 2005. 90:6373–9.

22.Lee X., Gao M., Ji Y., Yu Y., Feng Y., Li Y, et al. Analysis of differential BRAF (V600E) mutational status in high aggressive papillary thyroid microca- rcinoma. Ann Surg Oncol. 2009. 16:240–5.

23.Xing M. BRAF mutation in papillary thyroid microcarcinoma. The promise of better risk management. Ann Surg Oncol. 2009. 16:801–3.