Significance Of BRAFV600E Mutation Research Articles

The Prognostic Significance of BRAF V600E Mutation in Papillary Thyroid Carcinoma

The Prognostic Significance of BRAF V600E Mutation in Papillary Thyroid Carcinoma

Prognostic Significance of BRAF V600E Mutation and CPSF2 Protein Expression in Papillary Thyroid Cancer.

The early-stage diagnosis of papillary thyroid cancer (PTC) has significantly increased in incidence worldwide without any beneficial impact on survival. In order to improve the risk assessment in PTC, we have conducted a retrospective study in which we analyzed the BRAF V600E mutation and CPSF2 protein expression as prognostic markers on archival tissue samples of 49 patients without (control group) and 97 patients with (study group) PTC metastases in the cervical lymph nodes at the time of initial diagnosis. Our aim was to correlate the BRAF V600E mutation and the expression of CPSF2 protein with the clinical and pathological features of PTC. The expression of CPSF2 protein was evaluated via immunohistochemistry and graded semi-quantitatively. The presence of the BRAF V600E mutation was determined via real-time polymerase chain reac-tion (PCR). CPSF2 protein < 3+ intensity expression was correlated with more frequent recurrences (Fisher-Freeman-Halton exact test; p = 0.010; 95% CI: 1.26-22.03), and patients who presented with the BRAF V600E mutation and CPSF2 protein expression < 3+ intensity had shorter disease-free survival (log-rank test; 105.0 months vs. 146.6 months; p < 0.001; HR 8.32, 95% CI: 2.91-23.83), whereas patients with PTC who had CPSF2 expression 3+ had longer disease-free survival in correlation with other lower intensity expressions of CPSF2 protein (log-rank test; 139.7 months vs. 129.6 months; p = 0.008). The multivariate analysis showed that younger patients with CPSF2 protein expression <3+ and the BRAF V600E mutation are at an increased risk for recurrence and require more intensive monitoring (Cox proportional hazards regression model; X2 = 17.5, df = 10, p = 0.025). Our results correlate the BRAF V600E mutation and CPSF2 protein expression with recurrence and disease-free survival as relevant prognostic factors for PTC.

Significance of BRAFV600E mutation in intra-axial brain tumor in Malaysian patients: case series and literature review.

To date, BRAF mutations in brain tumor patients have not been characterized in the Malaysian population. Based on the numerous reported studies, there are main mutations that exist in BRAF gene in various types of cancers. A missense mutation in codon 600of the BRAF nuclear oncogene (BRAFV600E) is the most prevalent hotspot point mutation that has been identified in multiple human malignancies. We here aimed to find out the frequency of BRAFV600E mutation in a series of Malaysian patients with brain tumors and if any association exists between BRAFV600E mutation and clinicopathological features of patients. Fresh frozen tumor tissue samples from 50Malaysian brain tumor patients were analyzed for BRAFV600E mutational status, and its correlation with clinicopathological features (including age, gender, and tumor localization such as intra-axial: within the brain substance or extra-axial: outside the brain substance) was examined. The overall BRAFV600E mutation frequency was determined to be 22% (in 11of 50patients). BRAFV600E was significantly correlated with the tumor location group, which shows BRAFV600E was more frequent in the intra-axial tumor than the extra-axial tumor group. In this study, we also observed that male patients were slightly more susceptible to BRAFV600E mutation, and this mutation was predominant in patients of the age group<40years. However, these parameters did not translate to statistical significance. The data demonstrate that BRAFV600E mutation is observed significantly more often in intra-axial brain tumor patients, which can serve as baseline information for further research on genetic alteration that occurs during brain tumor progression in the Malaysian population.

Clinicopathological Significance of BRAF V600E Mutation in Egyptian Colorectal Cancer Patients

Abstract Background: In Egypt, there is a rapid increase in Color-ectal Cancer (CRC) incidence with more aggressive course and younger age at presentation compared to western patients. Aim of Study: This study aimed to examine BRAF V600E mutation in Egyptian CRC patients. Material and Methods: This study is done by collaboration between Pathology and Clinical Oncology & Nuclear Medicine Departments, Faculty of Medicine, Menoufia University between January 2015 and August 2019 in which 81 CRC patients were studied. Expression of BRAF V600E protein was evaluated by immunohistochemistry. The results of the studied marker were correlated with different clinicopatho-logical parameters and survival data. Results: The frequency of BRAF V600E mutation was 51.9%. There was no statistical difference between different studied clinicopathological parameters including sidedness and BRAF V600E mutation. Regarding survival during this follow-up duration, no significant statistical differences were detected. Conclusion: In Egyptian CRC patients, BRAF V600E protein expression had no correlation with CRC prognosis. However, validation of our results in a larger sample size is necessary.

BRAF V600E mutation as a prognostic factor in cutaneous melanoma patients.

The prognostic significance of BRAF mutations in the natural course of melanoma is controversial. The aim of study was to assess the prognostic significance of BRAF V600E mutation in cutaneous melanoma patients. A total of 151 melanomas were included in the study. BRAF V600E mutation was detected using the real-time PCR. BRAF V600E mutation rate was 51%. BRAF mutation rate was higher for young patients (61.4%) and upper limbs (63.2%), trunk (59.3%) and head and neck (59.2%) were the most frequently afflicted sites in BRAF-mutant patients, whereas lower limbs were mostly affected in BRAF-wild patients (77.8%). Likewise, acral melanomas rarely harbored BRAF mutation (17.1%). The disease-free survivals regarding the entire and Stage III cohorts were longer in the BRAF-mutant group than in the BRAF-wild group (p = .006 and p = .004, respectively), whereas Stage I-II patients had no survival differences between BRAF statuses (p = .2). Likewise, BRAF-mutant patients had better overall survival (OS) time compared to BRAF-wild patients in all stages (p = .01), in Stage III (p = .01), and in Stage IV patients (p = .001). However, no differences between BRAF statuses were observed in Stage I-II melanomas (p = .3). In conclusion, BRAF V600E-mutant melanomas show favorable prognostic impact on both disease-free and OSs in all staged melanomas except local disease.

Clinical and prognostic significance of BRAF V600E mutation in non-metastatic cutaneous melanoma patients.

Because of the conflicting conclusions on BRAF mutations in the natural course of non-metastatic melanoma their prognostic significance is still controversial. The present study aims to assess the prevalence and prognostic significance of BRAF V600E mutation and apprehend its association with clinicopathologic features in stage I to III Turkish melanoma patients. A total of 93 adult stages I to III cutaneous primary melanoma patients were included in the study. BRAF V600E mutation was detected using the Real Time PCR. Median age was 52 years (range, 18 to 84) and 68.8% of the patients were men. Overall, BRAF V600E mutation was detected in 46.2% (43/93) of the patients. In stages I and II, trunk was the most frequently affected localization (47.1%) (p=0.05) and regression was found more prevalent in BRAF-mutant patients (38.5%) (p=0.05). Furthermore, males were predominant among stage III BRAF-mutant patients (80.8%) (p=0.05), and both superficially spreading histology subtype (45.0%) (p=0.05) and lower mitotic rate (36.4%) (p=0.02) also were more commonly associated with stage III BRAF-mutant patients. A significantly favorable relapse free survival was found in stage III node-positive BRAF-mutant patients (p=0.02), on the other hand BRAF status was not found to be associated with relapse free survival in stage I and stage II patients (p=0.3). Moreover, there was no overall survival association between stages and BRAF status (p=0.1 and p=0.2). In conclusion, there is no prognostic value of BRAF V600E mutation on overall survival in stage I-III melanoma patients, yet its presence might indicate a decreased risk for development of relapse and/or metastasis in stage III melanoma patients.

The Significance of BRAFV600E Mutation in Thyroid Cancer in Terms of Novel Targeted Therapies - Overview of Current Knowledge and Studies.

About 50% of papillary thyroid cancers, the most common type of all thyroid malignancies, harbor the BRAFV600E mutation. The prognostic value of this mutation is still under debate, but according to many studies, the BRAF mutation significantly downregulates genes involved in the iodine metabolism of tumor follicular cells. This mutation can be also found in some dedifferentiated and anaplastic thyroid cancers, which raises the issue of the selective advantage of novel targeted therapies. The aim of this review is to discuss the significance of the BRAF mutation mostly in radioiodine-refractory thyroid cancers (RR-TC) with respect to recent preclinical and clinical studies reporting the results of different RAF and MEK inhibitors. BRAF mutation detection in progressive RR-TC could play a role in decision-making of targeted therapies in the near future. So far, only multi-kinase inhibitors (sorafenib and lenvatinib) are legally accepted. On the other hand, for patients with disseminated BRAF mutant malignant melanoma or lung cancer, selective treatments with RAF and MEK inhibitors (vemurafenib, dabrafenib, and trametinib) are available. A crucial advantage of these inhibitors in the treatment of thyroid cancer is their ability to restore expression of the genes involved in iodine metabolism in cancer cells that have lost this ability, thus opening the door for radioiodine treatment again. Key words thyroid cancer - BRAF mutation - biological therapy - tyrosine kinase inhibitor - MEK inhibitor The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 4. 6. 2018 Accepted: 1. 8. 2018.

Prevalence and Clinicopathologic Significance of BRAF V600E Mutation in Chinese Multiple Myeloma Patients

BackgroundPrevious studies in Western countries demonstrated BRAF V600E mutation only in a small subset of multiple myeloma (MM) patients. However, the prevalence and clinicopathologic significances of this mutation remain unclear in Chinese MM patients. Patients and MethodsWe studied diagnostic bone marrow samples from 205 Chinese MM patients by allele-specific PCR to detect BRAF V600E mutation and by high-resolution melting assay to detect KRAS and NRAS mutations. The mutations were confirmed by independent assays. ResultsBRAF V600E mutation was found in 9.3% of the cases, the highest prevalence hitherto reported. In addition, the mutation was significantly associated with hypercalcemia and a male predominance but not with aggressive extramedullary diseases or a high serum creatinine level as reported in Western studies. Importantly, BRAF V600E mutation was an adverse prognostic factor for overall survival in younger MM patients by subgroup analysis. Concurrent analysis of RAS mutations highlighted differential alteration spectrum of RAS signaling between Chinese and Western MM, which may suggest a unique myeloma-related genetic profile in Chinese patients. ConclusionOur study revealed a higher prevalence of BRAF V600E mutation in Chinese MM patients. The associated prognostic impacts on younger patients could be beneficial to risk stratification and potential application of BRAF-targeted therapies in Chinese MM management. This is the first large-scale study revealing the prevalence and clinicopathologic significances of BRAF V600E mutation in Chinese myeloma.

Prevalence and clinical significance of BRAFV600E mutation in patients with papillary thyroid cancer

Prevalence and clinical significance of BRAFV600E mutation in patients with papillary thyroid cancer

Significance of BRAF V600E Mutation and Cytomorphological Features for the Optimization of Papillary Thyroid Cancer Diagnostics in Cytologically Indeterminate Thyroid Nodules.

Ultrasound guided fine needle aspiration biopsy with cytologic analysis is an initial step in diagnostic of thyroid nodules. Unfortunately, up to 30% of biopsies are indeterminate and diagnostic surgery is required. The aim of this study was to estimate the diagnostic value of BRAF V600E mutation status combined with cytomorphological features for diagnosis of papillary thyroid cancer (PTC) in cytologically indeterminate thyroid nodules. A prospective study analyzed patients who had ultrasound suspicious thyroid nodules, underwent fine needle aspiration and cytological examination, and were classified according to the Bethesda system. Patients from indeterminate diagnostic categories were examined for BRAF V600E mutation and 22 cytomorphological features, and underwent thyroid surgery. A binary logistic regression model was used to evaluate the diagnostic utility. A total of 219 patients met study criteria. After histological examination, 77 (35.2%) patients were diagnosed with PTC and 142 (64.8%) with benign nodular thyroid disease. According to logistic regression model, significant features for PTC diagnosis were: liquid colloid consistency, papillary structures, eosinophilic colloid bodies, and BRAF V600E mutation. Risk groups classified by this model have sensitivity of 80.5% (95% CI: 69.9 to 88.7), specificity of 99.3% (95% CI: 96.1 to 100), positive predictive value of 98.4% (95% CI: 89.8 to 99.8), negative predictive value of 90.4% (95% CI: 85.7 to 93.7), and accuracy of 92.7% (95% CI: 88.4 to 95.8) for PTC diagnosis. Evaluation of BRAF V600E mutation status combined with cytomorphological features for diagnosis of PTC in cytologically indeterminate thyroid nodules can significantly improve diagnostic accuracy and reduce the number of diagnostic operations (calculator available at www.ptc-calc.we2host.lt).

Clinical significance of BRAF V600E mutation in 154 patients with thyroid nodules.

The aim of the present study was to investigate the prevalence of the BRAF V600E mutation in papillary thyroid carcinoma (PTC) patients from eastern coastal China and to determine whether it is correlated with the clinicopathological features of PTCs with or without current Hashimoto thyroiditis (HT). The BRAF V600E mutation status was analyzed in 206 thyroid nodules of 154 patients undergoing thyroidectomy using polymerase chain reaction and bi-directional sequencing. Multivariate analysis was performed to investigate the association of the BRAF V600E mutation with clinicopathological features. Thyroid nodules were classified as PTC, nodular goiter (NG), adenomatoid nodule, adenoma and HT. The BRAF V600E mutation was observed in 61.5% of PTCs analyzed; it was also detected in one normal tissue adjacent to PTC and one NG. One patient exhibited double mutations in the BRAF gene; the BRAF V600E mutation in the PTC lesion and the BRAF K601E mutation in the contralateral NG lesion. Patients harboring the BRAF V600E mutation had higher thyroid stimulating hormone levels (2.453±1.464 vs. 1.966±1.296 mIU/l), a reduced occurrence of papillary thyroid microcarcinoma (55.0 vs. 88%), and a higher occurrence of lymph node metastasis (LNM; 42.5 vs. 16.0%) compared with those with wild-type BRAF (all P<0.05). Binary logistic regression analysis revealed that the BRAF V600E mutation was associated with LNM of PTC (hazard ratio, 5.051; 95% confidence interval, 1.068-23.893; P=0.041). Conversely, no association was identified between the BRAF V600E mutation and HT (38.5 vs. 67.3%, χ2=3.656, P=0.056). Thus, in regional PTCs, the BRAF V600E mutation was prevalent, suggesting that it may be an early and phenotypically defining molecular event in PTC, and may represent an independent factor that predicts LNM.

Lack of Association ofBRAFMutation With Negative Prognostic Indicators in Papillary Thyroid Carcinoma

Papillary thyroid carcinoma (PTC) is the most common endocrine neoplasm. B-type raf kinase (BRAF) V600E mutation has been proposed as a negative prognostic indicator in PTC, and patients harboring it should receive more aggressive initial therapy. To assess the significance of BRAF V600E mutation in PTC in the largest US sample to date. We identified patients from our institution's pathology archives diagnosed as having PTC and meeting criteria for BRAF mutation testing. Medical records were analyzed for BRAF status (positive or negative) and a list of standardized clinicopathologic features. A total of 429 patients with PTC at an academic medical center. Clinicopathologic features in patients with PTC with and without BRAF mutation. Of 429 cases with PTC, 314 (73.2%) were positive for the BRAF mutation and 115 (26.8%) tested negative. BRAF mutation was significantly associated with tumor margin positivity (P = .03) and lymph node metastasis (P = .002) on univariate analysis but not on multivariate study. BRAF mutation was a predictor of male sex (odds ratio [OR], 3.2; 95% CI, 1.4-7.2), total thyroidectomy (OR, 2.6; 95% CI, 1.1-6.2), and a negative predictor of follicular variant PTC (OR, 0.1; 95% CI, 0.1-0.4). There was no significant association between BRAF positivity and tumor multicentricity, lymphovascular invasion, extranodal extension, central neck involvement, advanced stage (stage III or IV), and distant metastasis. BRAF V600E mutation has been extensively studied in relation to negative prognostic indicators in PTC, with no consistent relationship emerging. Two recent meta-analyses showed an overall association between BRAF status and aggressive disease features and called for tailoring treatment plans in patients accordingly. In this, the largest US study to date, BRAF status was not significantly associated with most clinicopathologic features suggestive of more aggressive disease.

Clinicopathologic significance of BRAF V600E mutation in papillary carcinomas of the thyroid

AbstractBACKGROUND.Numerous studies have investigated the clinical significance of BRAF mutation in papillary thyroid carcinoma (PTC). However, there have been conflicting data on the usefulness of BRAF mutation as a prognostic marker of PTC. To address this controversy, the frequency of the BRAF mutation and the associations between BRAF mutation and clinicopathologic parameters in PTC were evaluated by meta‐analysis.METHODS.The relevant published studies were reviewed according to the defined selection criteria. The effect sizes of outcome parameters were estimated by odds ratio or weighted mean difference.RESULTS.The current meta‐analysis included 12 studies with a total of 1168 patients. The frequency of the BRAF mutation was 49%. The BRAF mutation was associated with histologic subtype, the presence of extrathyroidal extension, and higher clinical stage, but not with age, sex, race, or tumor size.CONCLUSIONS.The effect of the BRAF mutation on the poor prognosis of PTC patients was evident from the current meta‐analysis. The detection of the BRAF mutation may be used as an important prognostic marker of patients with PTC. Cancer 2007. © 2007 American Cancer Society.