The Association of the BRAF(V600E) Mutation With Prognostic Factors and Poor Clinical Outcome in Papillary Thyroid Cancer

Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.
Cancer (Impact Factor: 4.89). 04/2012; 118(7):1764-73. DOI: 10.1002/cncr.26500
Source: PubMed


The effects of the BRAF(V600E) mutation on prognostic factors and poor clinical outcomes in papillary thyroid cancer (PTC) have not been fully quantified. The authors performed comprehensive meta-analysis to assess the strength of associations between these conditions and the BRAF(V600E) mutation.
The authors identified the clinical studies that examined the association of the BRAF(V600E) mutation in surgical specimens with clinicopathologic outcomes between January 2003 and October 2010 using the Medline database. One hundred thirty-one relevant studies were hand-searched. The authors selected 27 studies that included 5655 PTC patients. They calculated the pooled odds ratios (ORs) or risk ratios with 95% confidence intervals (CIs) for each study using a random effect model.
The average prevalence rate of the BRAF(V600E) mutation was 49.4%. In 26 studies, compared with the patients who had the wild-type BRAF genes, the PTC patients with the BRAF(V600E) mutation had increased ORs of an extrathyroidal invasion (OR, 2.14; 95% CI, 1.68-2.73), a lymph node metastasis (OR, 1.54; 95% CI, 1.21-1.97), and an advanced TNM stage (OR, 2.00; 95% CI, 1.61-2.49). In 8 studies, patients with the mutation had 2.14-fold increased risk of recurrent and persistent disease (95% CI, 1.67-2.74). The associations were generally consistent across the different study populations.
This meta-analysis demonstrates that the BRAF(V600E) mutation is closely related to the high-risk clinicopathological factors and poorer outcome of PTC. The results obtained here suggest that the BRAF(V600E) mutation should be considered as a poor prognostic marker in PTC and may lead to better management for individual patients.

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    • "The mutations in the above genes are closely related to specific demographic or clinicopathologic characteristics, including smoking habits, gender, clinical stage, and tumor histology [12], [13]. This information may be useful for the selection of patients for treatment with specific gene inhibitors. "
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    ABSTRACT: Background BRAF mutations have been well described in non-small cell lung cancer (NSCLC) for several years, but the clinical features of patients harboring BRAF mutations are still not well described. We performed a meta-analysis to identify common clinical features in NSCLC patients carrying BRAF mutations. Methods We identified clinical studies that examined the association between BRAF mutations and features of NSCLC within PubMed, Embase and ISI Science Citation Index database up to October 2013. The effect size of clinical features was estimated by odds ratios (ORs) with 95% confidence interval (CI) for each study, using a fixed-effects or random-effects model. Results Ten studies with a total of 5599 NSCLC patients were included. There was a 3% (170/5599) BRAF mutation rate. BRAF mutations in NSCLC were significantly associated with adenocarcinomas (ADCs) (compared with non-ADCs, OR = 4.96, 95%CI = 2.29–10.75). There were no significant differences in gender, smoking and stage in patients with and without BRAF mutations. The BRAFV600E mutation was more frequent in women than non-BRAFV600E mutations (OR = 0.27, 95%CI = 0.12–0.59), and was closely related to never smokers (OR = 0.14, 95%CI = 0.05–0.42). Conclusions These findings have important implications for the prediction of the NSCLC sub-types more accurately combined with other genetic changes.
    Full-text · Article · Jun 2014 · PLoS ONE
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    • "In recent years, the study of the molecular mechanisms of PTC has demonstrated that the BRAF gene mutation is a significant event in the process of this disease. The V600E mutation of the BRAF gene was identified in 28–83% of PTC specimens, however, no mutations were observed in normal thyroid tissue and tissue from patients with benign thyroid disease (4,8–11). A large number of studies have demonstrated that the BRAF gene mutation is associated with pathological features, including patient age, extrathyroidal invasion, lymph node metastasis and tumor stage, which aid in determining patient prognosis (5,6,12–14). "
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    ABSTRACT: The aim of the present study was to investigate the prevalence of the BRAF V600E mutation in papillary thyroid carcinoma (PTC) and to determine the correlation between this mutation and indicators of poor prognosis and outcome in patients with PTC. The BRAF V600E mutation status was analyzed in 187 tumor samples using the multiplex allele-specific PCR method. Univariate and multivariate analyses were performed to investigate the association of the BRAF V600E mutation with clinical features and patient outcome. The sensitivity of the multiplex allele-specific PCR combined with denaturing high-performance liquid chromatography reached ~1%. The BRAF V600E mutation was observed in 63.6% (119/187) of tumor tissues, predominantly in PTC specimens, and no BRAF mutation was identified in other benign-type thyroid diseases. The univariate analysis indicated that the BRAF V600E mutation was associated with age, tumor stage and prognosis (P<0.05). In addition, the frequency of the BRAF V600E mutation was significantly different in the central (75.3%) and lateral neck (49.3%) lymph nodes of patients with lymph node metastasis. Multivariate logistic regression analysis showed that the BRAF V600E mutation (HR, 2.471; 95% CI, 1.149-5.312) and lymph node metastasis (HR, 3.003; 95% CI, 1.027-8.771) are independent factors that predict tumor prognosis. Thus, the BRAF V600E mutation is an independent risk factor that may be used to predict thyroid cancer persistence/recurrence.
    Full-text · Article · Feb 2014 · Oncology letters
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    • "In a recent meta-analysis, the prevalence of BRAF mutations varied in different reports (28.8%–81.0%) and the average prevalence rate of BRAF mutations was 49.4% [12]. BRAF mutations in Chinese populations show a higher prevalence compared with the average prevalence rate of BRAF. "
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    ABSTRACT: Background: The molecular work-up of thyroid nodules from fine needle aspiration samples has given clinicians a new level of diagnostic information. The aim of the present study was to evaluate the utility of molecular analysis in thyroid fine needle aspiration samples from a Chinese population. Methods: Specimens were collected from thyroid nodules by fine needle aspiration. Cytology diagnosis and genes analysis were performed and correlated with histology outcome. Results: A total of 83 patients with thyroid nodules were enrolled, including 20 benign lesions and 63 papillary carcinomas. BRAF and RAS mutations and RET/PTC gene rearrangements were found in 65.1%, 0%, and 1.6% of papillary carcinomas, respectively. No gene alterations were found in benign lesions. The combination of BRAF testing and cytology improved the accuracy of cytology from 69.9% to 89.2% (P < 0.05). Moreover, BRAF testing confirmed 82.4% of papillary carcinomas with suspicious cytology and identified 33.3% of papillary carcinomas with atypia cytology. Conclusions: Of the three candidate markers, BRAF testing showed diagnostic utility in fine needle aspiration. Combining BRAF testing with cytology improves the accuracy of fine needle biopsy. Those who have positive BRAF and malignant or suspicious malignant cytology can undergo thyroidectomy without a frozen section.
    Full-text · Article · Jan 2014 · Disease markers
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