Skip to main content
PMC home page
International Journal of Clinical and Experimental Medicine logoLink to International Journal of Clinical and Experimental Medicine
. 2015 Dec 15;8(12):22246–22253.

The BRAF V600E mutation predicts poor survival outcome in patients with papillary thyroid carcinoma: a meta analysis

Jianhua Li 1, Shuijun Zhang 1, Shouhua Zheng 1, Danhua Zhang 1, Xinguang Qiu 1
PMCID: PMC4729986  PMID: 26885200

Abstract

Introduction: There have been contradictory data on whether or not BRAF V600E mutation should be regard as a poor prognosis predictor of papillary thyroid carcinoma (PTC). To settle down the conflict, this metaanalysis is prepared to clarify the present prognostic role of BRAF V600E mutation in patients with PTC. Methods and materials: The relevant published researches were incorporated according to the defined inclusion/exclusion criteria from PubMed. The effect sizes of outcome parameters were estimated by hazard ratios (HRs). Results: The current meta-analysis included 19 researches with a total of 6087 patients. We have found that patients with BRAF V600E mutation have a poor overall survival (the pooled HR=2.91, 95% confidence interval (CI): 1.35-6.29). Furthermore, subgroup analysis of the recurrence-free survival (RFS) of PTC patients by races indicated that BRAF V600E mutation predicts poor RFS of patients (the pooled HR=1.63, 95% CI: 1.37-1.93), both Caucasian (the pooled HR=1.57, 95% CI: 1.30-1.90) and Asian (the pooled HR=1.91, 95% CI: 1.28-2.87). Conclusions: The poor prognosis predicted role of BRAF V600E mutation in PTC was certified from the current meta-analysis. The BRAF V600E mutation may be used as a prognostic predictor of patients with PTC.

Keywords: Thyroid, thyroid papillary carcinoma (PTC), BRAF V600E mutation, meta-analysis

Introduction

As a common malignant tumor type of endocrine system, thyroid papillary carcinoma (PTC) including several subtypes such as common conventional PTC, follicular-variant PTC [1]. Compared to other types of malignancy, PTC is relatively a highly curable disease. PTC patients usually have high rate of overall 10-year survival (>90%), however, the main troubles of patients with PTC are regional recurrences and distant metastases [2]. To evaluate the prognosis of patients, several clinicopathologic factors were implemented, including age (>45 years old), gender (male), lymph nodes metastasis, extra-thyroidal extension, distant metastasis, aggressive histological subtype and advanced disease stages [3].

In addition, some biochemical markers (especially the BRAF V600E mutation) also been used to predict the cancer associated prognosis of PTC patients. As we known that, the BRAF V600E mutation is the most common mutation of PTC and associated with activation of the mitogen activated protein Kinase signaling pathway [4]. Numerous researches have revealed the BRAF V600E mutation statue in different subtypes of PTC, furthermore, estimated the correlation between the BRAF V600E mutation statue and various clinicopathologic factors of patients with PTC. And a recent study have pooled the reported data and conducted a meta-analysis to comprehensively evaluate the relationship between BRAF mutation and clinicopathological features of PTC [5]. Researchers [5] displayed that BRAF mutation is associated with male gender, LNM, stage, extra-thyroidal extension, tumor size, multifocality, classic PTC, and tall-cell variant PTC in PTC.

However, there is still conflicting about whether or not the BRAF V600E mutation could be a poor prognosis predictor of PTC patients. Some studies found that there have no significant relationship between the BRAF V600E mutation and PTC prognosis [6]. But other researches implied that the BRAF V600E mutation predicts poor overall survival (OS) and/or recurrence-free survival (RFS) of PTC patients [7]. For comprehensively understanding the role of the BRAF V600E mutation in PTC prognosis, it’s necessary for us to conduct a meta-analysis to quantitatively pool the reported data and completely explore the relationship between the BRAF V600E mutation and survival of PTC patients.

Methods and materials

Database and retrieval strategy

Because of its comprehensive coverage fraction of published researches, we used PubMed (http://www.ncbi.nlm.nih.gov/pubmed) as our target database for reference retrieval. The retrieval strategy involving the following keywords variably combined by “BRAF V600E mutation”, “thyroid”, “thyroid papillary carcinoma”, “carcinoma”, “survival outcomes” and “prognosis”.

Eligibility criteria

Inclusion criteria: (I) the target disease is thyroid papillary carcinoma; (II) the prognostic role of the BRAF V600E mutation was studied including overall survival (OS), progression free survival or disease free survival (PFS/DFS); (III) the latest or most informative single article was included when articles were derived from the same authors/groups. Exclusion criteria: (I) these article types are excluded: review, letter, laboratory research, or mechanism study; (II) the article is duplicated; (III) it lacked critical original data for meta-analysis.

Data extraction and Statistical analysis

The above references were screened according to the inclusion/exclusion criteria, by two authors. The reported data about the relationship between the BRAF V600E mutation and survival outcomes (OS, RFS and DFS) of PTC patients were extracted, the data types including reported survival data, the Kaplan-Meier (K-M) curves or HR and 95% CI. Also, the baseline characteristics of eligible articles were extracted by the other two researchers independently. The K-M curves’ data was extracted by Engauge Digitizer 4.1 (http://sourceforge.net). The multivariate cox hazard regression analysis data is first choice, if cannot obtained, univariate Cox hazard regression analysis or K-M survival curves of survival outcomes were instead, then reported survival data was the last choice for HR (95% CI) calculation.

STATA 11.0 (STATA Corporation, College Station, TX) was used to conduct the current meta-analysis. Heterogeneity was defined as P<0.05 or I2≥50%, a fixed effect model was used for pooled HRs calculation. On the contrary, if heterogeneity was fine (P≥0.05, I2<50%), a random effect model was used for pooled HRs calculation. If the pooled HR>1 and the 95% CI exclude 1, it indicated a significant worse outcome for the case group compared to the control group. The publication bias was tested by Begg’s test and Egger’s test, P<0.05 indicating that potential publication bias existed.

Results

Eligible articles filtration process

After total two steps of filtration, 19 articles [6-24] were recognized as finial eligible articles (Figure 1). At the first step, we initial included 305 references after retrieved the database of PubMed. Then 275 articles were excluded after reading the titles and abstracts. Among them, 68 articles were not associated with the prognostic role of the BRAF V600E mutation in PTC. 51 articles were review articles. 50 articles were excluded because they were focused on mechanism researches. 42 articles were excluded because they were not referred to the BRAF V600E mutation and/or PTC. 39 articles were just referred to diagnosis studies. 15 articles were case report articles, 5 articles were meta-analysis articles and the other 5 articles were not published in English. At the second step, 30 articles were included for comprehensive filtration, and 11 articles were further excluded because 5 articles were not associated with the prognostic role of the BRAF V600E mutation in PTC, 3 articles have no enough original data for meta-analysis and 3 articles were published by the same authors/groups. The baseline characteristics of eligible articles were listed in Table 1.

Figure 1.

Figure 1

Open in a new tab

Reference filtration procedures of the present meta-analysis.

Table 1.

The baseline characteristics of included references

Ref. Ethnic Accounts Follow up Survival outcomes Attitudes of BRAF mutation Study type Measurement of BRAF mutation
Niederer-Wüst SM et al. 2015 Caucasian 116 2-252 mon. OS/RFS Insignificance Retrospective PCR
Daliri M et al. 2014 Asian 69 12-192 mon. OS/RFS Insignificance Prospective SSCP
McKelvie PA et al. 2013 Caucasian 77 20-192 mon. OS/RFS Insignificance Prospective C-PCR
Ito Y et al. 2014 Asian 766 13-191 mon. OS/RFS Insignificance Retrospective PCR
Elisei R et al. 2012 Caucasian 319 5.3±0.8 yr. DFS Poor prognosis Prospective SSCP
Pelttari H et al. 2012 Caucasian 51 16 yr. RFS Insignificance Retrospective Allelic specific PCR with Scorpions rt-PCR
Guerra A et al. 2012 Caucasian 168 3-195 mon. RFS Insignificance Retrospective BigDye terminator sequencing and pyrosequencing
Elisei R et al. 2008 Caucasian 102 15 yr. OS/DFS Poor prognosis Retrospective SSCP
Kim TY et al. 2006 Asian 203 10 yr. DFS Poor prognosis Retrospective PCR amplification and direct sequencing
Huang FJ et al. 2014 Asian 214 12-50 mon. RFS Poor prognosis Prospective Sanger sequencing
Henke LE et al. 2015 Caucasian 508 8.0 yr. OS/RFS Insignificance Retrospective SSCP
Prescott JD et al. 2012 Caucasian 205 5.0 yr. RFS Poor prognosis Retrospective SSCP
Danilovic DL et al. 2014 Caucasian 178 33.5±7.2 mon. RFS Poor prognosis Retrospective Re-PCR genotyping technique
He G et al. 2014 Asian 187 24 mon. RFS Poor prognosis Retrospective Allelic specific PCR
Xing M et al. 2015 Caucasian 2099 13-67 mon. RFS Poor prognosis Retrospective BigDye terminator sequencing and pyrosequencing
Xing M et al. 2005 Caucasian 219 14 yr. RFS Poor prognosis Retrospective BigDye terminator sequencing and pyrosequencing
Kebebew E et al. 2007 Caucasian 314 72±33 mon. RFS Poor prognosis Retrospective BigDye terminator sequencing and pyrosequencing
Russo M et al. 2014 Caucasian 103 56.9±14.1 mon. RFS Insignificance Retrospective PCR
Pelizzo MR et al. 2014 Caucasian 189 1-156 mon. RFS Insignificance Retrospective SSCP
Open in a new tab

Months, mon.; Overall survival, OS; Recurrence-free survival, RFS; Year, yr.; Disease-free survival, DFS; polymerase chain reaction, PCR; PCR-single-strand conformation polymorphism analysis.

OS

Six articles listed the relationship between the BRAF V600E mutation and OS of PTC patients. The heterogeneity have not been found (P=0.666, I2=0.0%), and a fixed effect model was used. We found that the pooled HR (95% CI) is 2.91 (1.35, 6.29) (Figure 2).

Figure 2.

Figure 2

Open in a new tab

The pooled hazard ratio (HR, 95% CI) between the BRAF V600E mutation and overall survival (OS) of PTC patients.

RFS

Only two articles have reported the DFS data, however the remaining articles are all reported the RFS data. For convenience of meta-analysis, we have combined DFS data and RFS data to calculate the pooled HR (95% CI). The heterogeneity test revealed that P=0.130 and I2=27.4%, therefore a fixed effect model was used. We found that the pooled HR (95% CI) is 1.63 (1.37, 1.93) (Figure 3). Furthermore, subgroup analysis indicated that BRAF V600E mutation predicts poor RFS of patients, both Caucasian (the pooled HR=1.57, 95% CI: 1.30-1.90) and Asian (the pooled HR=1.91, 95% CI: 1.28-2.87) (Figure 3).

Figure 3.

Figure 3

Open in a new tab

The pooled hazard ratio (HR, 95% CI) between the BRAF V600E mutation and relapse-free survival (RFS) of PTC patients, based on subgroup analysis of races (Asian and Caucasian).

Publication bias

We have not found any publication bias through Begg’s funnel plot (Figure 4) and Egger’s test. The P value of Egger’s test is 0.069. In addition, we have conducted sensitivity analysis both for RFS and OS, to exam their stability. And the results were displayed in Supplementary Figure 1. A is the result for OS, and B is for RFS. We cannot found instability of results from the sensitivity analysis.

Figure 4.

Figure 4

Open in a new tab

The Begg’s funnel plot revealed little publication bias between the included references.

Discussion

Even though various types of meta-analysis have been conducted to evaluate the relationships between the BRAF V600E mutation and clinicopathologic characteristics of PTC patients. There have no associated meta-analysis which was implemented to analysis the correlation between the BRAF V600E mutation and long term survival of PTC patients, including OS and RFS. As we known that, the present meta-analysis is initially implemented to evaluate the correlation between the BRAF V600E mutation and long term survival of PTC patients. Although there have no consistent opinions about whether or not the BRAF V600E mutation statue of PTC patients correlated with poor long term survival (OS and/or RFS). After pooled survival data of included articles, we found that the BRAF V600E mutation statue of PTC patients (either Asian or Caucasian) significantly predicts poor survival outcomes (both OS and RFS).

Several mechanisms have been demonstrated to try to explain the poor prognostic role of the positive BRAF V600E mutation statue in PTC patients. First of all, BRAF V600E mutation may result in the excessive activation of RAS/BRAF/MAPK signal pathway, which was believed to act as a critical role in the tumorigenesis and progression of PTC. Animal experiments [25] discovered that normal rat thyroid cells with BRAF V600E mutation were likely to promote tumor invasion by expressing certain gene products and degradating the extracellular matrix of PTC. In addition, researchers also found that the BRAF V600E mutation in PTC was correlated with transportation and metabolism of iodide, and resulted in radioiodine treatment failure [26]. Furthermore, the BRAF V600E mutation induced silence of several tumor-suppressor genes and further promoted the invasiveness of PTC. Xing et al. [27] discovered that the BRAF V600E mutation in PTC was correlated with methylation of following tumor suppressor genes including tissue inhibitor of metalloproteinase-3 (TIMP3), SLC5A8, death-associated protein kinase (DAPK), and retinoic acid receptor b2 (RARb2).

In addition to the PTC prognosis prediction, the BRAF V600E mutation also has critical value in diagnosis and treatment of PTC patients. A number of studies [28] have demonstrated that the sensitivity, specificity, negative predictive value and positive predictive value of fine-needle aspiration biopsy (FNAB) for PTC were all been significantly improved after combined analysis of BRAF V600E mutation statue. And, some inhibitors have been developed to inhibit the excessive activation of RAS/BRAF/MAPK signal pathway. These inhibitors including sorafenib, PLX4032, RAF265, PLX4720.

In summary, our meta-analysis indicates that the BRAF V600E mutation in PTC is significantly associated with poor survival outcomes including OS and RFS. The BRAF V600E mutation may be used as a prognostic predictor of patients with PTC. However, further large sample size and multicentric clinical researches should be carried out to confirm our findings.

Disclosure of conflict of interest

None.

Authors’ contribution

Study design: Xinguang Qiu, Jianhua Li; Document retrieval: Shuijun Zhang, Shouhua Zheng; Data selection: Jianhua Li, Shuijun Zhang, Danhua Zhang; Wrote the paper: Jianhua Li, Xinguang Qiu.

Supporting Information

ijcem0008-22246-f5.pdf (365.7KB, pdf)

References

  • 1.Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90. doi: 10.3322/caac.20107. [DOI] [PubMed] [Google Scholar]
  • 2.Schlumberger MJ. Papillary and follicular thyroid carcinoma. N Engl J Med. 1998;338:297–306. doi: 10.1056/NEJM199801293380506. [DOI] [PubMed] [Google Scholar]
  • 3.Neuhold N, Schultheis A, Hermann M, Krotla G, Koperek O, Birner P. Incidental papillary microcarcinoma of the thyroid-further evidence of a very low malignant potential: a retrospective clinicopathological study with up to 30 years of follow-up. Ann Surg Oncol. 2011;18:3430–3436. doi: 10.1245/s10434-011-1663-x. [DOI] [PubMed] [Google Scholar]
  • 4.Xing M. BRAF mutation in papillary thyroid cancer: pathogenic role, molecular bases, and clinical implications. Endocr Rev. 2007;28:742–762. doi: 10.1210/er.2007-0007. [DOI] [PubMed] [Google Scholar]
  • 5.Li C, Lee KC, Schneider EB, Zeiger MA. BRAF V600E mutation and its association with clinicopathological features of papillary thyroid cancer: a meta-analysis. J Clin Endocrinol Metab. 2012;97:4559–4570. doi: 10.1210/jc.2012-2104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Henke LE, Pfeifer JD, Ma C, Perkins SM, De-Wees T, El-Mofty S, Moley JF, Nussenbaum B, Haughey BH, Baranski TJ, Schwarz JK, Grigsby PW. BRAF mutation is not predictive of longterm outcome in papillary thyroid carcinoma. Cancer Med. 2015;4:791–799. doi: 10.1002/cam4.417. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Elisei R, Viola D, Torregrossa L. The BRAF (V600E) mutation is an independent, poor prognostic factor for the outcome of patients with low-risk intrathyroid papillary thyroid carcinoma: single-institution results from a large cohort study. J Clin Endocrinol Metab. 2012;97:4390–4398. doi: 10.1210/jc.2012-1775. [DOI] [PubMed] [Google Scholar]
  • 8.Niederer-Wüst SM, Jochum W, Förbs D, Brändle M, Bilz S, Clerici T, Oettli R, Müller J, Haile SR, Ess S, Stoeckli SJ, Broglie MA. Impact of clinical risk scores and BRAF V600E mutation status on outcome in papillary thyroid cancer. Surgery. 2015;157:119–125. doi: 10.1016/j.surg.2014.07.015. [DOI] [PubMed] [Google Scholar]
  • 9.Daliri M, Abbaszadegan MR, Bahar MM, Taghehchian N, Zakavi SR. The role of BRAF V600E mutation as a potential marker for prognostic stratification of papillary thyroid carcinoma: a long-term follow-up study. Endocr Res. 2014;39:189–193. doi: 10.3109/07435800.2013.879169. [DOI] [PubMed] [Google Scholar]
  • 10.McKelvie PA, Chan F, Yu Y, Arabi A, Yadollahi M, Ghafari A. The prognostic significance of the BRAF V600E mutation in papillary thyroid carcinoma detected by mutation-specific immunohistochemistry. Pathology. 2013;45:637–644. doi: 10.1097/PAT.0000000000000008. [DOI] [PubMed] [Google Scholar]
  • 11.Ito Y, Yoshida H, Kihara M, Kobayashi K, Miya A, Miyauchi A. BRAF (V600E) mutation analysis in papillary thyroid carcinoma: is it useful for all patients? World J Surg. 2014;38:679–687. doi: 10.1007/s00268-013-2223-2. [DOI] [PubMed] [Google Scholar]
  • 12.Pelttari H, Schalin-Jäntti C, Arola J, Löyttyniemi E, Knuutila S, Välimäki MJ. BRAF V600E mutation does not predict recurrence after longterm follow-up in TNM stage I or II papillary thyroid carcinoma patients. APMIS. 2012;120:380–386. doi: 10.1111/j.1600-0463.2011.02844.x. [DOI] [PubMed] [Google Scholar]
  • 13.Guerra A, Fugazzola L, Marotta V, Cirillo M, Rossi S, Cirello V, Forno I, Moccia T, Budillon A, Vitale M. A high percentage of BRAFV600E alleles in papillary thyroid carcinoma predicts a poorer outcome. J Clin Endocrinol Metab. 2012;97:2333–2340. doi: 10.1210/jc.2011-3106. [DOI] [PubMed] [Google Scholar]
  • 14.Elisei R, Ugolini C, Viola D, Lupi C, Biagini A, Giannini R, Romei C, Miccoli P, Pinchera A, Basolo F. BRAF (V600E) mutation and outcome of patients with papillary thyroid carcinoma: a 15-year median follow-up study. J Clin Endocrinol Metab. 2008;93:3943–3949. doi: 10.1210/jc.2008-0607. [DOI] [PubMed] [Google Scholar]
  • 15.Kim TY, Kim WB, Rhee YS, Song JY, Kim JM, Gong G, Lee S, Kim SY, Kim SC, Hong SJ, Shong YK. The BRAF mutation is useful for prediction of clinical recurrence in low-risk patients with conventional papillary thyroid carcinoma. Clin Endocrinol (Oxf) 2006;65:364–368. doi: 10.1111/j.1365-2265.2006.02605.x. [DOI] [PubMed] [Google Scholar]
  • 16.Huang FJ, Fang WY, Ye L, Zhang XF, Shen LY, Han RL, Wei Q, Fei XC, Chen X, Wang WQ, Wang S, Ning G. BRAF mutation correlates with recurrent papillary thyroid carcinoma in Chinese patients. Curr Oncol. 2014;21:e740–747. doi: 10.3747/co.21.2029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Prescott JD, Sadow PM, Hodin RA, Le LP, Gaz RD, Randolph GW, Stephen AE, Parangi S, Daniels GH, Lubitz CC. BRAF V600E status adds incremental value to current risk classification systems in predicting papillary thyroid carcinoma recurrence. Surgery. 2012;152:984–990. doi: 10.1016/j.surg.2012.08.039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Danilovic DL, Lima EU, Domingues RB, Brandão LG, Hoff AO, Marui S. Pre-operative role of BRAF in the guidance of the surgical approach and prognosis of differentiated thyroid carcinoma. Eur J Endocrinol. 2014;170:619–625. doi: 10.1530/EJE-13-0944. [DOI] [PubMed] [Google Scholar]
  • 19.He G, Zhao B, Zhang X, Gong R. Prognostic value of the BRAF V600E mutation in papillary thyroid carcinoma. Oncol Lett. 2014;7:439–443. doi: 10.3892/ol.2013.1713. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Xing M, Westra WH, Tufano RP, Cohen Y, Rosenbaum E, Rhoden KJ, Carson KA, Vasko V, Larin A, Tallini G, Tolaney S, Holt EH, Hui P, Umbricht CB, Basaria S, Ewertz M, Tufaro AP, Califano JA, Ringel MD, Zeiger MA, Sidransky D, Ladenson PW. BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab. 2005;90:6373–6379. doi: 10.1210/jc.2005-0987. [DOI] [PubMed] [Google Scholar]
  • 21.Xing M, Alzahrani AS, Carson KA, Shong YK, Kim TY, Viola D, Elisei R, Bendlová B, Yip L, Mian C, Vianello F, Tuttle RM, Robenshtok E, Fagin JA, Puxeddu E, Fugazzola L, Czarniecka A, Jarzab B, O’Neill CJ, Sywak MS, Lam AK, Riesco-Eizaguirre G, Santisteban P, Nakayama H, Clifton-Bligh R, Tallini G, Holt EH, Sýkorová V. Association between BRAF V600E mutation and recurrence of papillary thyroid cancer. J. Clin. Oncol. 2015;33:42–50. doi: 10.1200/JCO.2014.56.8253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Kebebew E, Weng J, Bauer J, Ranvier G, Clark OH, Duh QY, Shibru D, Bastian B, Griffin A. The prevalence and prognostic value of BRAF mutation in thyroid cancer. Ann Surg. 2007;246:466–470. doi: 10.1097/SLA.0b013e318148563d. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Pelizzo MR, Dobrinja C, Casal Ide E, Zane M, Lora O, Toniato A, Mian C, Barollo S, Izuzquiza M, Guerrini J, De Manzini N, Merante Boschin I, Rubello D. The role of BRAF (V600E) mutation as poor prognostic factor for the outcome of patients with intrathyroid papillary thyroid carcinoma. Biomed Pharmacother. 2014;68:413–417. doi: 10.1016/j.biopha.2014.03.008. [DOI] [PubMed] [Google Scholar]
  • 24.Russo M, Malandrino P, Nicolosi ML, Manusia M, Marturano I, Trovato MA, Pellegriti G, Frasca F, Vigneri R. The BRAF (V600E) mutation influences the short-and medium-term outcomes of classic papillary thyroid cancer, but is not an independent predictor of unfavorable outcome. Thyroid. 2014;24:1267–1274. doi: 10.1089/thy.2013.0675. [DOI] [PubMed] [Google Scholar]
  • 25.Mesa C Jr, Mirza M, Mitsutake N, Sartor M, Medvedovic M, Tomlinson C, Knauf JA, Weber GF, Fagin JA. Conditional activation of RET/PTC3 and BRAFV600E in thyroid cells is associated with gene expression profiles that predict a preferential role of BRAF in extracellular matrix remodeling. Cancer Res. 2006;66:6521–6529. doi: 10.1158/0008-5472.CAN-06-0739. [DOI] [PubMed] [Google Scholar]
  • 26.Ricarte-Filho JC, Ryder M, Chitale DA, Rivera M, Heguy A, Ladanyi M, Janakiraman M, Solit D, Knauf JA, Tuttle RM, Ghossein RA, Fagin JA. Mutational profile of advanced primary and metastatic radioactive iodine-refractory thyroid cancers reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1. Cancer Res. 2009;69:4885–4893. doi: 10.1158/0008-5472.CAN-09-0727. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Hu S, Liu D, Tufano RP, Carson KA, Rosenbaum E, Cohen Y, Holt EH, Kiseljak-Vassiliades K, Rhoden KJ, Tolaney S, Condouris S, Tallini G, Westra WH, Umbricht CB, Zeiger MA, Califano JA, Vasko V, Xing M. Association of aberrant methylation of tumor suppressor genes with tumor aggressiveness and BRAF mutation in papillary thyroid cancer. Int J Cancer. 2006;119:2322–2329. doi: 10.1002/ijc.22110. [DOI] [PubMed] [Google Scholar]
  • 28.Seo JY, Choi JR, Moon HJ, Kim EK, Han KH, Kim H, Kwak JY. Clinical Implication of Highly Sensitive Detection of the BRAFV600E Mutation in Fine-Needle Aspirations According to the Thyroid Bethesda System in Patients with Conventional Papillary Thyroid Carcinoma. Ann Otol Rhinol Laryngol. 2015;124:392–399. doi: 10.1177/0003489414560433. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ijcem0008-22246-f5.pdf (365.7KB, pdf)

Articles from International Journal of Clinical and Experimental Medicine are provided here courtesy of e-Century Publishing Corporation

RESOURCES