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BRAF mutations in an Italian cohort of thyroid cancers
Abstract
Recently, a somatic point mutation of the BRAF gene (V599E) has been identified as the most common genetic event in papillary thyroid carcinoma (PTC) with a variable frequency (about 25-70%) in different series from USA, Japan, Portugal and Ukraine.
In the present study, the genetic analysis of BRAF in an Italian cohort of 65 thyroid tumours with corresponding normal tissues and 21 thyroid benign disorders is reported.
For BRAF analysis, the somatic DNA was PCR amplified by means of specific intronic primers and PCR products were directly sequenced. Statistical analyses were obtained by means of Fisher's exact test.
All mutations detected involved a T > A transversion at 1796 (V599E) and were heterozygous. Overall, BRAF(V599E) mutation was found in 18/56 (32.1%) PTCs. According to the histological type of the tumour, the mutation was present in 38.3% of cases of conventional PTC (18/47), in 0/6 follicular variant of PTC, in 0/3 oncocytic variant of PTC. No BRAF mutations were detected either in five follicular carcinomas, or in four poorly differentiated or undifferentiated cancers or in benign thyroid disorders. No statistically significant correlation of BRAF mutation with patient age and gender, with multicentricity of the tumour, with the lymphocytic infiltration of the tissue, with the stage and with the recurrence rate, was found. BRAF(V599E) tended to be associated, although not significantly, with a greater volume and extension of the tumour and with lymph-nodal metastases at surgery.
In conclusion, the present study on the first Italian series of thyroid cancers shows a frequency of 38.3% of BRAF(V599E) in the classical variant of PTC, confirming the key role of this mutation in promoting tumourigenesis.
... This leads to valine being substituted by glutamate. It has been reported that the frequency of the BRAF V600E mutation varies greatly (28-83%) (5)(6)(7)(8). ...
... Moreover, thyroid cancer was induced in transgenic mice with thyroid tissue that specifically expressed the BRAF V600E protein, suggesting that BRAF protein activation is closely related to the occurrence of PTC. The role and potential mechanism of BRAF mutation in the occurrence and development of PTC has become an area of great interest (7). It is currently believed that the V600E mutation is located in the activation region of BRAF (CR3). ...
... Thus far, the BRAF V600E mutation rates reported from different studies are varied (6)(7)(8), ranging from 28 to 83%, which is primarily related to epidemiological factors such as different geographical and ethnic backgrounds. In addition, some studies suggested it was related to the subtype distribution of PTC. ...
The aim of the present study was to investigate the association between the BRAF V600E mutation and ultrasound features of the thyroid in papillary thyroid carcinoma (PTC). Fresh thyroid carcinoma tissue and paracarcinoma tissue were obtained from 34 patients undergoing surgery for PTC. The BRAF V600E mutation was detected by PCR amplification and direct DNA sequencing. The thyroid ultrasound results were compared between patients with and without the BRAF V600E mutation. Eighteen out of 34 cases were identified with the BRAF V600E mutation (52.9%), while 16 cases did not have the BRAF V600E mutation (47.1%). Additionally, no BRAF V600E mutation was detected in paracarcinoma tissue in the 34 cases. The results of ultrasound imaging suggested that there were no significant differences in tumor size, whether the border was clear, or in tumor calcification (presence or absence) between patients with and without BRAF V600E mutation (P>0.05). The BRAF V600E mutation rate was high in patients with PTC. There was no significant correlation between BRAF V600E mutation and thyroid ultrasound features. Thyroid ultrasound features are therefore unable to predict the presence of the BRAF V600E mutation in patients with PTC.
... %. Many authors have reported that the BRAF V600E mutation is associated with aggressive clinical features and poor prognosis; however, others have suggested that there is no association between the BRAF V600E mutation and clinicopathologic features in PTCs [5][6][7]. Thus, it remains controversial whether the BRAF V600E mutation closely correlates with poor clinical characteristics in PTC, and it is necessary to confirm the association between BRAF V600E and the clinical prognosis of PTC using meta-analysis. ...
... In instances where the same study cohort was used in multiple articles, either the most recent or the most appropriately informative single article was included. For example, Fugazzola et al. [6] included only data from a single institute and contained a cohort overlapping with Fugazzola et al. [8]; therefore, we used the latter study for our analysis. ...
... A total of 997 abstracts and titles of full-text papers obtained through electronic searches were deemed relevant and examined in detail. Following this detailed review, 63 studies met our inclusion/exclusion criteria; these studies contributed 20,764 patients with PTC to this metaanalysis [6,. The main features of the 63 eligible studies that investigated prognostic factors are summarized in Table 1. ...
Background
The objective of this study is to perform a meta-analysis to evaluate the associations between the BRAFV600E mutation status and aggressive clinicopathological features and poor prognostic factors in papillary thyroid cancer. MethodsA literature search was performed within the PubMed, MEDLINE, Web of Science databases, and EMBASE databases using the Medical Subject Headings and keywords from January 2003 to July 2015. Individual study-specific odds ratios and confidence intervals were calculated, as were the Mantel-Haenszel pooled odds ratios for the combined studies. ResultsSixty-three studies of 20,764 patients were included in the final analysis. Compared with wild-type BRAF, the BRAFV600E mutation was associated with aggressive clinicopathological factors, including extrathyroidal extension, higher TNM stage, lymph node metastasis, and recurrence, and was associated with reduced overall survival; however, there was no significant association between the presence of BRAF mutation and distant metastasis. ConclusionsBRAF mutations are closely associated with aggressive clinicopathological characteristics and poorer prognosis in papillary thyroid cancer. Accordingly, aggressive treatment should be considered for papillary thyroid cancer patients with BRAF mutation.
... In the last years, new BRAF mutations have been described in different PTC subtypes (Table 26.6). Many studies have compared the BRAF V600E mutation distribution in different malignant (FTC, MTC, ATC) and benign thyroid pathologies (MNG, Graves' disease, FA) and in normal thyroid tissue, concluding that this mutation is specific for PTC and PDTCs derived from PTCs (Namba et al., 2003;Nikiforova et al., 2003a;Xu et al., 2003;Fugazzola et al., 2004;Hayashida et al., 2004;Puxeddu et al., 2004;Kim et al., 2005b;Xing, 2005;Zhu et al., 2005;Castro et al., 2006;Erickson et al., 2007;Cañadas Garre, 2010;Chuang et al., 2010). Exceptionally, the presence of the BRAF V600E mutation has been described in pathologies different from PTC: in 1 case of 73 patients with FTC (Kebebew et al., 2007), an FTC cell line (Xu et al., 2003), and in 2 cases of atypical nodular hyperplasia (Chung et al., 2006;Kim et al., 2011). ...
... According to previous observations, BRAF V600E mutation is commonly associated with PTCs showing papillary architecture (conventional PTC, tall cell PTC, Warthin PTC, microPTC), with a frequency ranging between 26% and 83% (Fugazzola et al., 2004;Trovisco et al., 2005a;Xing, 2005;Xing et al., 2005;Zhu et al., 2005;Riesco-Eizaguirre et al., 2006;Lupi et al., 2007;Costa et al., 2008;Frasca et al., 2008;Oler and Cerutti, 2009;Gao et al., 2012). BRAF V600E mutation prevalence is particularly high (55%-100%) in a high aggressive variant of PTC, the tall cell subtype Zhu et al., 2005;Lupi et al., 2007;Cañadas Garre, 2010;Cañadas Garre et al., 2011), whereas it is relatively low (7%-25%) in the follicular variant (Nikiforova et al., 2003a;Fugazzola et al., 2004Fugazzola et al., , 2006Salvatore et al., 2004;Trovisco et al., 2004Trovisco et al., , 2005aXing, 2005;Xing et al., 2005;Castro et al., 2006;Giannini et al., 2007;Riesco-Eizaguirre et al., 2006;Kebebew et al., 2007; Lupi et al., 2007;Costa et al., 2008;Oler and Cerutti, 2009). ...
... According to previous observations, BRAF V600E mutation is commonly associated with PTCs showing papillary architecture (conventional PTC, tall cell PTC, Warthin PTC, microPTC), with a frequency ranging between 26% and 83% (Fugazzola et al., 2004;Trovisco et al., 2005a;Xing, 2005;Xing et al., 2005;Zhu et al., 2005;Riesco-Eizaguirre et al., 2006;Lupi et al., 2007;Costa et al., 2008;Frasca et al., 2008;Oler and Cerutti, 2009;Gao et al., 2012). BRAF V600E mutation prevalence is particularly high (55%-100%) in a high aggressive variant of PTC, the tall cell subtype Zhu et al., 2005;Lupi et al., 2007;Cañadas Garre, 2010;Cañadas Garre et al., 2011), whereas it is relatively low (7%-25%) in the follicular variant (Nikiforova et al., 2003a;Fugazzola et al., 2004Fugazzola et al., , 2006Salvatore et al., 2004;Trovisco et al., 2004Trovisco et al., , 2005aXing, 2005;Xing et al., 2005;Castro et al., 2006;Giannini et al., 2007;Riesco-Eizaguirre et al., 2006;Kebebew et al., 2007; Lupi et al., 2007;Costa et al., 2008;Oler and Cerutti, 2009). The meta-analysis of Lee et al. (2007) confirmed that BRAF V600E mutation is associated with PTC histological subtype, being more prevalent in the conventional (frequency: 59.1%, odds ratio [OR] = 3.521) and tall cell subtypes (frequency: 79.1%, OR = 4.319) than in the follicular variant (frequency: 16.9%, OR = 0.153), indicating that this mutation is associated with papillary growth pattern. ...
... Associations have been shown between BRAF V600E mutations and poor prognosis, and it has been demonstrated that the BRAF V600E mutation correlates with a higher relapse rate and disease-specific mortality [7][8][9][10][11][12][13][14]. However, several recent studies in various countries have failed to reproduce these findings [15][16][17][18]. Although the reason for this discrepancy between different studies remains unclear, regional or ethnic backgrounds and differences in therapeutic strategies may offer some explanation. ...
... We also evaluated presence of the BRAF V600E mutation, which has been reported by some as a poor prognostic factor in PTC [7][8][9][10][11][12][13][14][15][16][17][18]. Previous studies on BRAF V600E in Japanese PTC patients showed BRAF V600E to be a rather common event, occurring in 29-52 % of cases, but not in association with high-risk clinicopathological factors or patient prognosis [49][50][51]. ...
The prognostic value of BRAFV600E and TERT promoter mutation in papillary thyroid carcinoma (PTC) is controversial. We examined alterations in BRAFV600E and TERT promoter by PCR-direct sequencing in PTC of 144 Japanese patients. Alternative lengthening of telomeres was examined as another mechanism of telomere maintenance by immunohistochemical staining for ATRX and DAXX. Of the clinicopathological characteristics, regional lymph node metastasis, extra-thyroid extension, multifocality/intrathyroidal spread, and advanced stage (III/V) were associated with shorter disease-free survival rate (DFSR). TERT promoter mutation was found in eight patients (6 %), and this was significantly associated with total thyroidectomy, multifocality/intrathyroidal spread, lymph node metastasis and advanced stage. The BRAFV600E mutation was found in 53 patients (38.2 %) but was not associated with any clinicopathological factors. TERT mutations were not correlated with BRAFV600E mutation status. TERT mutation-positive tumors (TERT+) showed lower DFSR than BRAFV600E-mutation-positive tumors (BRAFV600E+), and TERT+/BRAFV600E+ tumors showed lower DFSR than BRAFV600E+ tumors. No cases showed loss of ATRX/DAXX expression by immunohistochemistry. TERT promoter mutations showed a lower prevalence in our series and appeared to be associated with aggressive behavior. In PTCs, telomerase activation by TERT promoter mutation might be more important than alternative lengthening of telomeres.
... The presence of this BRAF mutation is believed to be associated with particular factors of poor prognosis, such as lymph node metastases, extrathyroidal invasion, advanced disease stage, lack of tumor capsule [17][18][19] and, according to the last multicenter study of Xing et al., with an increased cancer-related mortality among PTC patients [20]. However there are studies contradicting these data [21][22][23]. Last data indicate on mutations in promoter of the TERT gene that, coexisting with BRAFV600E, may determine aggressive course of PTC and play key role in preoperative diagnostics [24,25]. ...
... w ramach wieloośrodkowego badania, podwyższoną śmiertelnością związaną z rakiem [20]. Są jednak prace, w których nie wykazano znamienności między występowaniem mutacji genu BRAF, a powyższymi czynnikami [21][22][23]. Ostatnie doniesienia wskazują na mutacje w promotorze genu TERT jako zmiany genetyczne, które towarzysząc mutacji BRAFV600E warunkują agresywny przebieg choroby i mogą odgrywać kluczową rolę w diagnostycznym postępowaniu przedoperacyjnym [24,25] [44]. ...
Thyroid carcinoma (TC) is the most common endocrine malignancy and its frequency is still rising. Papillary thyroid carcinoma (PTC) accounts 80% of all TC and usually is related to a very good prognosis. However, the standard therapeutic approaches are not always sufficient enough and the disease progression is observed. These data highlight the limitation of our understanding of molecular mechanisms underlying tumorigenesis and how they vary between individual patients. Over the last 19 years mouse models of thyroid cancers have been developed in order to give answers to questions about their genetic background, relations of key molecular events with fundamental for cancer pathways and many others. Among these models genetically engineered mice were of highest importance according to the input to knowledge about human tumorigenesis. In the present review most significant mouse models of PTC are described with particular emphasis on BRAFV600E-induced ones, for the sake of its frequency in PTC, relation to factors of poor prognosis and the fact that, since its identification, it became an attractive target in novel therapies. For presented mouse models phenotype consequences of particular genetic alterations are described as well as limitations of used method.
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... Importantly, BRAF genetic alterations have also been linked to the diminished capacity of tumors to capture I-131 and therapeutic ineffectiveness in the relapsed condition. 26,27 Lately, an additional pathway for the activation of BRAF has been uncovered. It entails chromosomal 7q reversal, which causes BRAF and the AKAP9 gene to fuse in-frame. ...
Thyroid cancer stands as the predominant malignancy within the endocrine system, comprising about 1% of newly identified cancer instances. Papillary Thyroid Cancer (PTC) is the predominant form of thyroid cancer, representing 80% or more of thyroid malignancies. Thyroid carcinoma harbours assorted genetic alterations which are highly prevalent, several of these characteristics are unique to this form of cancer. The conventional oncogenic genetic modifications frequently observed in thyroid carcinoma encompass RAS mutations RET/PTC rearrangements and PAX8-peroxisome proliferator-activated receptor g (PPARg) fusion oncogene. The lately discovered activating mutation in BRAF (the gene for the B-type RAF kinase, BRAF) the most widespread genetic modification in thyroid cancer (30-83%). RKIP (RAF kinase inhibitory protein) had formerly been delineated as a phospholipid binding protein. Mammalian RKIP/PEBP differs from other identified proteins and its role is still being clarified. RKIP over-expression can inhibit MEK interaction with RAF-1 and B-RAF. It plays a role in thyroid cancer progression and lymph node metastasis. So, elucidating mutational profile and protein expression of above cell signalling molecules will be very useful in determining a proper therapeutic target for anti-cancer molecules. Given that tumors often possess numerous genetic and cell signalling abnormalities, thus inhibiting a single signalling pathway is often therapeutically inefficacious, more success could be foreseen with agents directed against multiple cellular pathways.
By determining the genetic profile and protein expression of mentioned MAP Kinase pathway molecules new targets can be identified for chemotherapic drugs and novel strategies will be charted out to make modifications in the map kinase pathway with the aim to stop the occurrence and distant metastasis of thyroid cancer.
... (11). In cases negative for any mutations/fusions analyzed by PTC-MA assay, BRAFK601E mutation was investigated by direct sequencing of exon 15 (12), and AKAP9/BRAF and LMO7/BRAF fusions were analyzed on cDNA, as previously reported (13,14). ...
Radiofrequency ablation (RFA) is effective in the treatment of thyroid nodules, leading to a 50-90% reduction with respect to baseline. Current guidelines indicate the need for a benign cytology prior to RFA, though, on the other side, this procedure is also successfully used for the treatment of papillary microcarcinomas. No specific indications are available for nodules with an indeterminate cytology (Bethesda III/IV). We aimed to evaluate the efficacy of RFA in Bethesda III nodules without genetic alterations as verified by means of a custom panel. We have treated 33 patients (mean delivered energy 1069±1201 Joules/ml of basal volume) with Bethesda III cytology, EU-TIRADS 3-4, and negative genetic panel. The mean basal nodular volume was 17.3±10.7 ml. Considering the whole series, the mean volume reduction rate (VRR) was 36.8±16.5% at 1 month, 59.9±15.5% at 6 months and 62±15.7% at 1-year follow-up. The sub-analysis done in patients with 1 and 2 years follow up data available (n=20 and n=5, respectively), confirmed a progressive nodular volume decrease. At all-time points, the rate of reduction was statistically significant (P<0.0001), without significant correlation between the VRR and the basal volume. Neither cytological changes nor complications were observed after the procedure.
In conclusion, RFA is effective in Bethesda III, oncogene-negative nodules, with reduction rates similar to those obtained in confirmed benign lesions. This procedure represents a good alternative to surgery or active surveillance in this particular class of nodules, regardless of their initial volume. A longer follow-up will allow to evaluate further reduction or possible regrowth.
... BRAF V600E mutations have been shown to be a sensitive but not specific marker for aggressive thyroid cancers, as they are more likely to be associated with aggressive histopathological features such as capsular invasion, extrathyroidal extension, and nodal metastasis [8,9]. In contrast, several studies did not report any association between this mutation and aggressive histopathological features of PTCs [10,11]. Allele frequency (AF) is the number of mutant molecules divided by the total number of wild-type molecules at a specific location in the genome. ...
Simple Summary
This study aimed to investigate the relationship between the allele frequency (AF) of the BRAF V600E mutation and the histopathological features of papillary thyroid cancer (PTC), with a focus on its aggressive behavior. The research involved a retrospective chart review of 44 patients with BRAF V600E-positive thyroid malignancies, and the results indicated a direct correlation between BRAF V600E AF and aggressive histopathological behavior. Specifically, nodules with aggressive PTC features exhibited a significantly higher mean AF (25.8%) compared to the non-aggressive group (10.25%). Additionally, a significant difference in mean AF was observed between patients with positive sentinel lymph nodes (29%) and those with negative sentinel lymph nodes (17.8%). Although different histopathological subtypes showed varying mean AF values, they did not exhibit a statistically significant relationship. The study findings suggest that the BRAF V600E mutation, in combination with AF, can serve as a pre-operative indicator to help thyroid specialists determine the extent of thyroidectomy and the necessity of lymph node dissection, providing valuable insights for the management of thyroid malignancies in clinical practice.
Abstract
Background: A BRAF V600E mutation in papillary thyroid cancer (PTC) has been shown to be associated with aggressive behavior. Nevertheless, not all BRAF V600E PTCs behave aggressively. Allele frequency (AF) is the number of mutated molecules divided by the total number of wild-type molecules at a specific location in the genome. The relationship between BRAF V600E AF and the histopathological features of thyroid malignancies is not well understood. We hypothesized that the BRAF V600E AF will correlate directly with aggressive histopathological behavior. The aim of this study was to examine this relationship. Methods: A retrospective chart review was performed for patients treated for BRAF V600E thyroid malignancies from 2019 to 2022 at McGill University tertiary care hospitals (n = 317). Patients with BRAF V600E-positive malignancies that included information on AF were included (n = 44). The correlation between AF and tumor histopathological features was analyzed. Results: Out of the 44 nodules with a BRAF V600E mutation, those with aggressive features of PTC had a mean AF of 25.8%, which was significantly higher than the non-aggressive group with a mean AF of 10.25% (p = 0.020). Additionally, there was a statistically significant difference in mean AF between patients with a positive sentinel LN (29%) and those with a negative sentinel LN (17.8%) (p = 0.021). Classical PTC was present in 29.5% (13/44) of nodules, with a mean AF of 15.6%. The tall cell subtype was found in 64% (28/44) of nodules, with a mean AF of 23%. Solid and hobnail subtypes were less common in this study, and there was no statistically significant relationship between AF and histopathological subtypes (p = 0.107). Nodules smaller than 1cm had a mean AF of 13.3%, while nodules ranging from 1 2cm had a mean AF of 20.6%, and those larger than 2cm had a mean AF of 27.7%. However, no statistical difference was observed between AF and nodule size (p = 0.160). Conclusion: In this study, BRAF V600E mutations in conjunction with AF help to determine whether thyroid malignancies will display aggressive behavior. This pre-operative finding can help thyroid specialists to determine the extent of thyroidectomy and whether lymph node dissection is required.
... Whether it was the entire cohort or with the exclusion of the 35-55 age group, the obtained BRAF V600E positivity rate of approximately 80% is consistent with the prevalence found in the Korean population. In contrast, a significantly lower prevalence has been reported in Western countries, typically around 32-51% [7,[36][37][38]. The study results may provide an advantage in tailoring diagnosis and treatment for younger patients in Western countries, where the incidence of BRAF V600E mutation is lower than that in Asian countries. ...
Simple Summary
This study investigated the impact of age and BRAFV600E mutation on papillary thyroid cancer (PTC) recurrence. Among patients with BRAFV600E-positive PTC, those under 35 years of age had a significantly higher risk of recurrence than those over 55 years. However, in BRAFV600E-negative patients, age had no impact on the risk of recurrence. These findings emphasize the importance of considering age and mutation status in tailoring PTC treatment and follow-up.
Abstract
BRAFV600E positivity is associated with increased aggressiveness of papillary thyroid cancer (PTC), and age is an important prognostic factor. However, the association between age and BRAFV600E positivity and the recurrence risk has not been investigated. This study aimed to investigate the impact of age on recurrence between patients with BRAFV600E-positive and -negative PTC. Patients with PTC who underwent initial thyroid surgery between January 2010 and December 2018 at Seoul St. Mary’s Hospital (Seoul, Republic of Korea) were retrospectively reviewed. The BRAFV600E-positive (n = 1768) and BRAFV600E-negative groups (n = 428) were divided into two subgroups: younger (<35 years) and older groups (≥55 years). In the BRAFV600E-positive group, the younger group exhibited higher lymphatic and vascular invasion rates, more positive lymph nodes, higher lymph node ratios, and higher recurrence rates than the older group (5.9% vs. 2.1%). Multivariate analysis revealed that age, lymphatic invasion, and N category were significant risk factors in the BRAFV600E-positive group. In the BRAFV600E-positive group, the younger group had a higher recurrence risk than the older group (OR, 2.528; 95% confidence interval, 1.443–4.430; p = 0.001). In the BRAFV600E-negative group, age had no impact on recurrence risk. These results contribute to tailored treatment strategies and informed patient management.
... In our study, BRAF V600E mutation was present in 61.6% of conventional papillary thyroid cancers (PTCs) and in 56.3% of other histological types; these results are similar to the results of other previous studies when classified according to histological subtypes. [30][31][32] Our study showed no association between the BRAF V600E gene mutation and the disease stage, which is consistent with the study by Peuxeddu et al. 33 In contrast, other studies reported that BRAF V600E mutations are associated with stage III and IV diseases. 34 A multicenter study with a large number of patients showed that patients with stages III and IV had a significantly higher rate of BRAF mutation than the non-mutant group (P = .007). ...
Background
The B-type rafkinase (BRAF) V600E gene mutation plays an important role in the pathogenesis, diagnosis, and prognosis of thyroid carcinoma. This study was conducted to investigate the rate of the BRAF V600E mutation, the relationships between the BRAF V600E gene mutation and some immunohistochemical markers, and recurrence rate in patients with differentiated thyroid cancer.
Method
The study was conducted by a descriptive and longitudinal follow-up method on 102 thyroid carcinoma patients at 103 Military Hospital, Hanoi, Vietnam. All patients were identified with the BRAF V600E gene mutation by real-time polymerase chain reaction.
Results
The rate of BRAF V600E gene mutation in patients with thyroid cancer was 60.8%. Patients with BRAF V600E gene mutation had a significantly higher rate of positive cyclooxygenase 2 (COX-2) and Ki67 markers than those without the mutation (COX-2: odds ratio [OR] = 2.93; 95% confidence interval [CI] = 1.27-6.74, P = .011; Ki67: OR = 3.41; 95% CI = 1.31-8.88, P = .01). A statistically significant relationship was identified between the rate of BRAF V600E mutation and the rate of positive Hector Battifora mesothelial 1 (HBME-1) (B = −1.040; P = .037) and COX-2 (B = −1.123; P = .023) markers. The recurrence rate in patients with BRAF V600E gene mutation was significantly higher than that in those without the mutation ( P = .007). The mean of the recurrence time of patients with BRAF V600E mutation was significantly lower than that in those without the mutation ( P = .011).
Conclusions
A high prevalence of BRAF V600E gene mutation was found in thyroid carcinoma patients. The rates of positive HBME-1, COX-2, and Ki67 markers were significantly correlated to BRAF V600E gene mutation. Patients with BRAF V600E gene mutation showed a significantly higher relapse rate and earlier relapse time than those without the mutation.
... However, only 10-35% of undifferentiated ATCs harbor BRAF V600E [1,[9][10][11][12][13][14][15]. Interestingly, not all TCs with BRAF V600E are associated with poor prognosis [16][17][18][19]. We propose that this distinction may be related to BRAF V600E cellular trafficking. ...
The presence of mutant BRAF V600E correlates with the risk of recurrence in papillary thyroid cancer (PTC) patients. However, not all PTC patients with BRAF V600E are associated with poor prognosis. Thus, understanding the mechanisms by which certain PTC patients with nuclear BRAF V600E become aggressive and develop resistance to a selective BRAF inhibitor, PLX-4032, is urgently needed. The effect of nuclear localization of BRAFV600E using in vitro studies, xenograft mouse-model and human tissues was evaluated. PTC cells harboring a nuclear localization signal (NLS) of BRAFV600E were established and examined in nude mice implanted with TPC1-NLS-BRAFV600E cells followed by PLX-4032 treatment. Immunohistochemical (IHC) analysis was performed on 100 PTC specimens previously confirmed that they have BRAFV600E mutations. Our results demonstrate that 21 of 100 (21%) PTC tissues stained with specific BRAFV600E antibody had nuclear staining with more aggressive features compared to their cytosolic counterparts. In vitro studies show that BRAFV600E is transported between the nucleus and the cytosol through CRM1 and importin (α/β) system. Sequestration of BRAFV600E in the cytosol sensitized resistant cells to PLX-4032, whereas nuclear BRAFV600E was associated with aggressive phenotypes and developed drug resistance. Proteomic analysis revealed Arp2/3 complex members, actin-related protein 2 (ACTR2 aliases ARP2) and actin-related protein 3 (ACTR3 aliases ARP3), as the most enriched nuclear BRAFV600E partners. ACTR3 was highly correlated to lymph node stage and extrathyroidal extension and was validated with different functional assays. Our findings provide new insights into the clinical utility of the nuclear BRAFV600E as a prognostic marker for PTC aggressiveness and determine the efficacy of selective BRAFV600E inhibitor treatment which opens new avenues for future treatment options.
... 18 However, other studies have failed to show this association. 23,24 Among patients in Korea 25 and Japan, 26 the BRAF V600E mutation was not found to be a significant prognostic factor for tumor aggressiveness; this suggests the potential role of racial and genetic differences in terms of disease presentation. 27 Currently, we have limited data on molecular biomarkers in Filipino patients with thyroid cancers. ...
Background and Objective. Epidemiological studies have shown that Filipinos have a higher prevalence of well differentiated thyroid cancer and a higher rate of recurrence. The BRAF V600E mutation has been proposed as a potential prognostic marker in aggressive papillary thyroid cancers. In this study, we determined whether this mutation is a risk factor for tumor recurrence in papillary thyroid cancer among Filipinos.
Methods. We conducted an age and sex-matched case-control study of patients with papillary thyroid cancer; we had two groups – with and without tumor recurrence – of 14 patients each, with at least a 5-year follow-up. We extracted the DNA samples from the patients’ (paraffin-embedded) tumor biopsy tissue blocks from thyroidectomy specimens, then detected the BRAF V600E mutation using polymerase chain reaction. The McNemar’s test for difference of proportions in paired data was used to determine the association of BRAF V600E mutation with recurrence.
Results. The BRAF V600E mutation was found in 57.14% of all cases. We found a prevalence of 64.29% among those with recurrence and 50.00% among those without recurrence, with no significant difference between the two groups (p = 0.688).
Conclusion. Our study showed the BRAF V600E mutation was not associated with recurrence. We encountered several limitations: we had limited data regarding molecular methodologies in the Philippine setting, we had a small sample size, and therefore we could not study other parameters (e.g., tumor characteristics, lymph node metastasis, stage of disease). We hope that this paves the way for future studies and collaborations to establish the role of BRAF V600E in Filipinos with papillary thyroid tumor recurrence.
... MAPK hyperactivation is crucial in PTC initiation through point mutations of the BRAF oncogene. BRAF, a member of the RAF family of serine/threonine protein kinases downstream of RAS, is mutated with a higher prevalence in PTC (29-83%) [26][27][28][29]. PI3K/mTOR/Akt pathway activation has a central role in FTC development. ...
Thyroid cancer is the most common (~90%) type of endocrine-system tumor, accounting for 70% of the deaths from endocrine cancers. In the last years, the high-throughput genomics has been able to identify pathways/molecular targets involved in survival and tumor progression. Targeted therapy and immunotherapy individually have many limitations. Regarding the first one, although it greatly reduces the size of the cancer, clinical responses are generally transient and often lead to cancer relapse after initial treatment. For the second one, although it induces longer-lasting responses in cancer patients than targeted therapy, its response rate is lower. The individual limitations of these two different types of therapies can be overcome by combining them. Here, we discuss MAPK pathway inhibitors, i.e., BRAF and MEK inhibitors, combined with checkpoint inhibitors targeting PD-1, PD-L1, and CTLA-4. Several mutations make tumors resistant to treatments. Therefore, more studies are needed to investigate the patient’s individual tumor mutation burden in order to overcome the problem of resistance to therapy and to develop new combination therapies.
... Several researches have showed important relation between BRAF mutation and poor signs changes[13,26]. But this research results discrepancy with some articles like studies of BRAF mutation in an Italian and Japanese population[27,28]. In spite of this recent analyses which showed almost relationship between BRAF mutation and high risk of thyroid cancer especially PTC, that steps should be use to modify the first step treatments in BRAF -positive with PTC[29,30]. ...
OBJECTIVES Thyroid cancer Treatment decision-making is often guided by tumor tissue molecular analysis. The aim of this study was the detection of BRAF, NRAS and HRAS mutations in Georgian patients with thyroid cancer and determination of the frequency of these mutations in the respective populations. SETTING Diagnostic molecular laboratory located in Tbilisi, Georgia. PARTICIPANTS 116 patients with thyroid cancer participated in the study. PRIMARY AND SECONDARY OUTCOME MEASURES Genetic change is the main force of thyroid tumor development, based on new methods of managing thyroid cancer. The latest significant genetic discovery in thyroid cancer is the BRAF-T1799A (V600E) transformation (the gene for B-type RAF kinase, BRAF). Since the initial report of this breakthrough in thyroid cancer years ago, rapid progress has been made. The BRAF mutation is the most common genetic change in thyroid cancer. BRAF and NRAS mutations are frequent genetic alterations found in thyroid nodules. These molecular markers establish a differential diagnosis and facilitate clinical decision-making. Prevalence of thyroid nodule-associated mutations has not been studied in Georgia. We evaluated BRAF, NRAS and HRAS mutations in Georgian patients with indeterminate cytology or diagnosed with papillary thyroid cancer (PTC). RESULTS BRAF (V600E), NRAS (G12C, G12D, Q61R, and Q61K) and HRAS (G12C, G13R, and Q61R) were determined in the DNA extracted from fine needle aspirate specimens. In total, 116 patient samples were analyzed using competitive-specificTaqMan PCR (Cast PCR TM). In these samples, 36 were diagnosed as papillary thyroid carcinoma, and 80 were indeterminate by Bethesda system for reporting thyroid cytopathology (BSRTC III-V). BRAF (V600E) mutation was the most frequent genetic alteration found in 31% of all analyzed samples. Specifically, this mutation was present in 61% of PTC cases and 18% of cases classified as indeterminate (BSRTC III-V). NRAS mutations were present in 16% of PTC and 30% of indeterminate cytology samples. NRAS G12D and Q61R were most prevalent at 36.6% and 40% of all NRAS mutations. BSRTC IV category of indeterminate cytology had the highest frequency of NRAS mutations at 43%. From analyzed samples, HRAS (Q61R) mutation was present in only one PTC case.
... BRAF has been addressed as a prognostic marker in thyroid cancer in the literature, where associations were found with larger tumours, older age, miETE, and lymph node metastasis [37][38][39][40]. Nonetheless, several other works have refuted these associations [34,41,42] and in the present work we did not confirm the association of BRAF with worse prognostic features. ...
The presence of TERT promoter (TERTp) mutations in thyroid cancer have been associated with worse prognosis features, whereas the extent and meaning of the expression and activation of TERT in thyroid tumours is still largely unknown. We analysed frozen samples from a series of benign and malignant thyroid tumours, displaying non-aggressive features and low mutational burden in order to evaluate the presence of TERTp mutations and TERT mRNA expression in these settings. In this series, TERTp mutations were found in 2%, only in malignant cases, in larger cancers, and from older patients. TERT mRNA expression was detected in both benign and malignant tumours, with increased frequencies in the malignant tumours with aggressive histotypes, larger tumours, and from older patients. In benign tumours, TERT mRNA expression was found in 17% of the follicular thyroid adenoma (FTA) with increased levels of expression in smaller tumours and associated with the presence of thyroiditis. TERTp mutations and TERT mRNA expression are correlated with worse prognosis features in malignant thyroid tumours, whereas TERT mRNA expression in the benign tumours is associated with the presence of thyroiditis.
... We have also shown BRAF V600E mutation in 46% of PTC. Our finding has an intermediate position between Mediterranean countries and North American and some Far East countries [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] (Table 6). Some studies have close results to ours [28,29,30,35,36,38,39]. ...
Background
Papillary thyroid carcinoma (PTC) is the most common malignant thyroid neoplasm comprising 80–90% of all thyroid malignancies. Molecular changes in thyroid follicular cells are likely associated with the development of PTC. Mutations in serine/threonine-protein kinase (BRAF) and Rat sarcoma viral oncogene homolog (RAS) are commonly seen in PTC.
Methods
In total, 90 cases of PTC are randomly selected from archive paraffin blocks and 10μm sections were cut and processed for DNA extraction. BRAF V600E mutation and 8 types of KRAS mutations were investigated using Real Time PCR.
Results
BRAF V600E mutation was identified in 46% of PTC while KRAS mutations were seen in 11% of PTC. There was significant correlation between BRAF V600E mutation and PTC larger than 5cm in diameter, positive surgical margin and lymph node metastasis. BRAF V600E mutation was significantly higher in patients with less than 55-year of age than those more than 55-year of age. BRAF V600E mutation was significantly higher in patients with family history of thyroid cancer than those without. There was no significant difference in BRAFV600E mutation between males and females, PTC classic and follicular variants, unifocal and multifocal PTC. There was a significant higher percentage of BRAF V600E mutation in classic PTC than papillary microcarcinoma variant. There was no significant age, gender, histologic type, tumor size, lymph node metastasis, tumor focality, and surgical margin status differences between KRAS mutated and non-mutated PTC.
Conclusion
BRAF V600E and KRAS mutation are seen in a significant number of PTC in the UAE. BRAF mutation is significantly correlated with large tumor size, positive surgical margins and lymph node metastasis suggesting an association between BRAF V600E mutation and tumor growth and spread.
... BRAF, a member of the raf family of serine/threonine protein kinases, has been shown to be mutated and constitutively activated in ∼7% of all cancers. Prevalence of BRAF mutation in PTC varies among different series ranging from 29 to 83% (30)(31)(32)(33)(34)(35)(36)(37). Most recently, the TCGA reported 74.6% of BRAF mutations in PTC, of which 61.7% were V600E substitutions. ...
The incidence of thyroid cancer (TC) has increased worldwide over the past four decades. TC is divided into three main histological types: differentiated (papillary and follicular TC), undifferentiated (poorly differentiated and anaplastic TC), and medullary TC, arising from TC cells. This review discusses the molecular mechanisms associated to the pathogenesis of different types of TC and their clinical relevance. In the last years, progresses in the genetic characterization of TC have provided molecular markers for diagnosis, risk stratification, and treatment targets. Recently, papillary TC, the most frequent form of TC, has been reclassified into two molecular subtypes, named BRAF-like and RAS-like, associated to a different range of cancer risks. Similarly, the genetic characterization of follicular TC has been proposed to complement the new histopathological classification in order to estimate the prognosis. New analyses characterized a comprehensive molecular profile of medullary TC, raising the role of RET mutations. More recent evidences suggested that immune microenvironment associated to TC may play a critical role in tumor invasion, with potential immunotherapeutic implications in advanced and metastatic TC. Several types of ancillary approaches have been developed to improve the diagnostic value of fine needle aspiration biopsies in indeterminate thyroid nodules. Finally, liquid biopsy, as a non-invasive diagnostic tool for body fluid genotyping, brings a new prospective of disease and therapy monitoring. Despite all these novelties, much work remains to be done to fully understand the pathogenesis and biological behaviors of the different types of TC and to transfer this knowledge in clinical practice.
... [21] However, this association was variably reported in many studies, and the mutational status was reported to be not significantly associated with aggressive features and poor outcome. [11,12,[23][24][25][26][27][28][29] BRAF positivity did not correlate with known prognostic variables such as age, gender, number of lesions, histologic subtype, invasion, lymph nodal, and ETE in the present study. ...
... regions, ranging from 30% to 80%, [11][12][13][14] thereby raising the debate whether screening for BRAF mutations in settings with lower prevalence could, if at all, aid in increasing the diagnostic accuracy. Several investigators have also argued that if performed presurgically, then BRAF positivity would not only predict thyroid malignancy with a higher specificity but would also potentially guide the extent of initial surgical treatment. ...
Original Article backGrOund
... regions, ranging from 30% to 80%, [11][12][13][14] thereby raising the debate whether screening for BRAF mutations in settings with lower prevalence could, if at all, aid in increasing the diagnostic accuracy. Several investigators have also argued that if performed presurgically, then BRAF positivity would not only predict thyroid malignancy with a higher specificity but would also potentially guide the extent of initial surgical treatment. ...
Objective
Analysis of BRAF V600E mutation in thyroid fine needle aspirates (FNA) is an important adjunct to cytology, particularly among FNA placed in the “indeterminate category.” However, such a prospective evaluation of FNA obtained from patients with thyroid nodules has been lacking from India.
Material and Methods
FNA from 277 patients were prospectively evaluated for BRAF mutations by Sanger's sequencing. A subset of 30 samples was also analyzed by pyrosequencing using the PyroMark BRAF mutation kit.
Results
Overall, 27.2% of FNA samples were positive for mutations including 19 (35.8%) of the 53 histologically confirmed papillary thyroid carcinoma (PTC), 2 of the 25 follicular variants of PTC, and 1 anaplastic thyroid carcinoma. Only 1 (2.7%) of the 37 samples in the atypia of undetermined significance/follicular lesion of unknown significance category was BRAF positive. The sensitivity of cytology improved marginally from 67.1% to 68.3% when evaluated with BRAF. Further, a comparison of the clinicopathological characteristics of BRAF positive and negative PTCs showed a significant association (P = 0.05) between lymph node metastasis and BRAF positivity.
Conclusion
BRAF positivity was lower than that reported from East Asia with the test being useful in confirming malignancies among the suspicious of malignancy and malignant categories.
... It is also reported that the presence of BRAF mutation is associated with a decreased expression of thyroid specific genes like NIS and TPO, what results in the loss of sensitivity to radioiodine [6]. However, there are also contradicting studies, in which no significant association between BRAF V600E and poor prognosis is demonstrated [7,8]. ...
TERT promoter (TERTp) mutations are important factors in papillary thyroid carcinomas (PTCs). They are associated with tumor aggressiveness, recurrence, and disease-specific mortality and their use in risk stratification of PTC patients has been proposed. In this study we investigated the prevalence of TERTp mutations in a cohort of Polish patients with PTCs and the association of these mutations with histopathological factors, particularly in coexistence with the BRAF V600E mutation. A total of 189 consecutive PTC specimens with known BRAF mutational status were evaluated. TERTp mutations were detected in 8.5% of cases (16/189) with the C228T mutation being the most frequent. In six of the PTC specimens (3.2%), four additional TERTp alterations were found, which included one known polymorphism (rs2735943) and three previously unreported alterations. The association analysis revealed that the TERTp hotspot mutations were highly correlated with the presence of the BRAF V600E mutation and their coexistence was significantly associated with gender, advanced patient age, advanced disease stage, presence of lymph node metastases, larger tumor size, and tumor-capsule infiltration. While correlations were identified, the possibility of TERTp mutations being key molecular modulators responsible for PTC aggressiveness requires further studies.
... Unfortunately, only a few studies have studied the relationship between mutation positivity and survival outcomes, none of which are randomized. [29][30][31][32][33][34] This is largely due to the indolent biology of PTC, which necessitates the analysis of large number of patients with a long follow-up to observe any significant differences between them. ...
Introduction:
Molecular markers are increasingly being explored as a potential diagnostic and prognostic tool in patients with well-differentiated thyroid cancers and B-type Raf kinase (BRAF) V600E mutation has received a wide attention in this regard. Many clinical studies have demonstrated an association of BRAF V600E mutation with aggressive clinicopathologic characteristics and high tumor recurrence and mortality in patients with papillary thyroid cancers. Papillary thyroid cancers has been abbreviated and PTCs.
Aim:
The present single center study aims to assess the biological behavior of conventional papillary thyroid cancers. (PTC) with somatic BRAF V600E mutation.
Materials and methods:
Patients who were managed for well differentiated thyroid cancers during 2005-2006 were included in the study. BRAF V600E mutation analysis was done by real time polymerase chain reaction after extracting genomic DNA from the representative archived formalin fixed paraffin embedded tumor tissue.
Results:
Of the 79 patients of well-differentiated thyroid cancers included in the study, 31% harbored BRAF V600E mutation; the mutation prevalence was 39.6% in the cohort of conventional PTCs. Our study emphatically states that BRAF V600E mutation status is a significant predictor of adverse outcomes in patients with conventional PTCs.
Conclusion:
Our study further suggests a possible risk-stratified approach using age, BRAF V600E mutation status, and extrathyroidal spread, and this approach can be used to personalize the management of patients with conventional PTCs. The result of our study adds to the growing consensus that BRAF V600E mutational status should be analyzed in correlation with other molecular and clinicopathological prognostic factors for a better risk stratification.
... The BRAF mutation has been reported to be associated with poor prognosis owing to its aggressive clinical features, such as extra thyroidal invasion, lymph node (LN) metastasis, advanced tumor, node, and metastasis (TNM) stage, and nodal recurrence (5,7,8). However, the clinical significance of BRAF mutation for predicting poor PTC prognosis has been controversial in a way that a number of authors have reported this mutation was not associated with aggressive behavior or poor prognosis (9)(10)(11).Therefore, in this study, we evaluated the association between the BRAF mutation and pathologic aggressiveness (or the clinical significance) in the BRAF mutation patients with PTC. ...
... The following cases were evaluated: a. 23 non-consecutive PTCs harboring common genetic alterations (BRAFV600E, TERT G228A, TERT G250A, NRAS Q61R, NRAS Q61K, HRAS Q61K, RET/PTC1, RET/PTC3) recruited at Fondazione IRCCS Ca' Granda ( Table 1). All the alterations of the PTC samples were previously detected by Sanger sequencing, as already reported [4][5][6]. Samples were frozen tissues in 12 cases, and formalin-FFPE tissues in 11 cases. ...
Purpose:
We exploited the MassARRAY (MA) genotyping platform to develop the "PTC-MA assay", which allows the simultaneous detection of 13 hotspot mutations, in the BRAF, KRAS, NRAS, HRAS, TERT, AKT1, PIK3CA, and EIF1AX genes, and six recurrent genetic rearrangements, involving the RET and TRK genes in papillary thyroid cancer (PTC).
Methods:
The assay was developed using DNA and cDNA from 12 frozen and 11 formalin-fixed paraffin embedded samples from 23 PTC cases, together with positive and negative controls.
Results:
The PTC-MA assay displays high sensitivity towards point mutations and gene rearrangements, detecting their presence at frequencies as low as 5%. Moreover, this technique allows quantification of the mutated alleles identified at each tested locus.
Conclusions:
The PTC-MA assay is a novel MA test, which is able to detect fusion genes generated by genomic rearrangements concomitantly with the analysis of hotspot point mutations, thus allowing the evaluation of key diagnostic, prognostic, and therapeutic markers of PTC in a single experiment without any informatics analysis. As the assay is sensitive, robust, easily achievable, and affordable, it is suitable for the diagnostic practice. Finally, the PTC-MA assay can be easily implemented and updated by adding novel genetic markers, according to clinical requirements.
... The study was approved by the institutional review board of each center, and informed patient consent was obtained where required. For BRAF V600E mutation analysis, genomic DNA was isolated from primary PTC tumors and sequenced at exon 15 of the BRAF gene as described previously (21,22,(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34). BRAF mutation status was not used to affect the treatment decisionmaking. ...
Background:
Precise risk stratification-based treatment of solitary intrathyroidal papillary thyroid cancer (SI-PTC) that is larger than 1.0 cm and 4.0 cm or less is undefined.
Methods:
A genetic-clinical risk study was performed on BRAF V600E in 955 patients (768 women and 187 men) with SI-PTC, with median age of 46 years and median clinical follow-up time of 64 months at 11 medical centers in six countries. The chi-square test or, for analyses with small numbers, Fisher's exact test was performed to compare recurrence rates. Recurrence-free probability was estimated by Kaplan-Meier (KM) analysis, and the independent effect of BRAF mutation on the recurrence was analyzed by Cox regression and Cox proportional hazard analyses. All statistical tests were two-sided.
Results:
Recurrence of SI-PTC larger than 1.0 cm and 4.0 cm or less was 9.5% (21/221) vs 3.4% (11/319) in BRAF mutation vs wild-type BRAF patients, with a hazard ratio (HR) of 3.03 (95% confidence interval [CI] = 1.46 to 6.30) and a patient age- and sex-adjusted hazard ratio of 3.10 (95% CI = 1.49 to 6.45, P = .002). Recurrence rates of SI-PTC larger than 2.0 cm and 4.0 cm or less were 16.5% (13/79) vs 3.6% (5/139) in mutation vs wild-type patients (HR = 5.44, 95% CI = 1.93 to 15.34; and adjusted HR = 5.58, 95% CI = 1.96 to 15.85, P = .001). Recurrence rates of SI-PTC larger than 3.0 cm and 4 cm or less were 30.0% (6/20) vs 1.9% (1/54) in mutation vs wild-type patients (HR = 18.40, 95% CI = 2.21 to 152.98; and adjusted HR = 14.73, 95% CI = 1.74 to 124.80, P = .01). Recurrences of mutation-positive SI-PTC were comparable with those of counterpart invasive solitary PTC, around 20% to 30%, in tumors larger than 2.0 cm to 3.0 cm. BRAF mutation was associated with a statistically significant decrease in recurrence-free patient survival on KM analysis, particularly in SI-PTC larger than 2.0 cm and 4.0 cm or less. Similar results were obtained in conventional SI-PTC. The negative predictive values of BRAF mutation for recurrence were 97.8% (95% CI = 96.3% to 98.8%) for general SI-PTC and 98.2% (95% CI = 96.3% to 99.3%) for conventional SI-PTC.
Conclusions:
BRAF V600E identifies a subgroup of SI-PTC larger than 1.0 cm and 4.0 cm or less, particularly tumors larger than 2.0 cm and 4.0 cm or less, that has high risk for recurrence comparable with that of invasive solitary PTC, making more aggressive treatment reasonable.
... Certain studies considered that patients with the BRAF V600E mutation should receive LND in the central compartment (18,21,22). However, other studies reported that the correlation between BRAF V600E and tumor aggressiveness, involving LNM, was not evident (23,24). Thus, this divergence in the association between BRAF V600E and more aggressive clinicopathological characteristics deserves further in-depth investigation. ...
The association between central lymph node metastasis (LNM) and risk factors, including the presence of the BRAF mutation, BRAFV600E,in patients with papillary thyroid cancer (PTC) requires further investigation. A potent risk factor that can indicate LNM in different histological subtypes of PTC and in different preoperative central lymph node statuses also requires further research. A total of 287 patients with PTC who accepted thyroidectomy were included in the present study. Clinicopathological data of these patients were reviewed to examine the risk factors for central LNM through univariate and multivariate analyses. Overall, BRAFV600E in patients with cNO (subclinical nodal disease) and cNl (other than cNO) PTC was associated with central LNM. However, multivariate analyses demonstrated that BRAFV600E was not an independent risk factor in patients with cNl or cNO PTC. For patients with classical variant PTC (CVPTC), BRAFV600E was independently associated with central LNM. However, on further analysis, the association was only significant in patients with cNO CVPTC. For patients with follicular variant PTC (FVPTC) or aggressive variant PTC (AVPTC), the BRAFV600E mutation rate was not significantly different between patients with and without central LNM. In conclusion, BRAFV600E was an independent risk factor for central LNM overall in patients with PTC and in patients with CVPTC, particularly in patients with cNO CVPTC. However, BRAFV600E was not an independent risk factor for patients with FVPTC and AVPTC. Therefore, BRAFV600E provides varied clinical significance in different histological subtypes and preoperative central lymph node status.
... (6,10,) Although most of the studies proved a strong association between BRAF mutation and the high-risk clinicopathological features, there are studies that have failed to prove a significant association for which no definitive explanation could be given. (15)(16)(17)(18) Comparable to the previous studies, BRAF mutation was negative in multinodular goitre and diffuse thyromegaly in our study, which proves that it is highly specific for papillary carcinoma. This highlights the significance of using BRAF mutational analysis in fine needle aspiration specimens so as to decide on further management and to avoid unnecessary thyroidectomies. ...
... RET/PTC rearrangement and RAS gene mutations are responsible for *20% and 10%-15% of cases, respectively (6). The presence of BRAF mutations has been inconsistently associated with aggressive tumoral behavior and poor outcome (7)(8)(9)(10). ...
... Only in a few studies a relationship between the presence of the mutation and the decrease in disease-free survival was observed (26,28,34). Elisei et al. in 2008 demonstrated the relationship between the presence of BRAF mutation and a decrease in overall and disease-free survival in a group of 102 patients with the mean follow-up of 10 years or longer (28). ...
Papillary thyroid cancer (PTC) offers excellent prognosis, however relapse risk or persistent disease is related to ~30%. Currently, attention is paid to the possibility of patient group selection of different risk of unfavorable outcome to match a particular therapeutic approach. Therefore, interest in new prognostic and predictive markers known preoperatively is observed. BRAF V600E mutation is such a marker. Many studies analyzing the prevalence of the mutation and its relationship with other clinicopathological risk factors were reported but with controversial conclusions. The prognostic significance of BRAF mutation was confirmed by some single centre studies, a few meta-analyses and a large multicenter retrospective international study. They confirmed a correlation between the mutation and the risk of recurrence. The strongest argument against using BRAF mutation as an independent prognostic and predictive factor in PTC is its high prevalence (30-80%). At present it seems that BRAF mutation is one of the factors influencing the prognosis and it should be analyzed in correlation with other prognostic factors. The most recent ATA recommendations do not indicate a routine application of BRAF status for initial risk stratification in differentiated thyroid cancer due to a lack of evident confirmation of a direct influence of mutation on the increase in relapse risk. However, ATA demonstrates the continuous risk scale for the relapse risk assessment, considering BRAF and/or TERT status. At present, researchers are working on determining the role of BRAF mutation in patients from a low-risk group and its correlations with others molecular events. Currently, BRAF mutation cannot be used as a single, independent predictive factor. However, its usefulness in the context of other molecular and clinico-pathological risk factors cannot be excluded. They may be used to make modern prognostic scales of relapse risk and be applied to individualized diagnostic and therapeutic strategy for PTC patients.
... fs frame shift a Change to a stop codon range, as the prevalence of BRAF mutations in ATC has been found to range from 0 to 50 % in different series [14,[36][37][38][39][40][41]. The Cancer Genome Atlas (TCGA) screening of more than 400 PTC showed that the majority of PTC samples (~60 %) harbored a BRAF V600E mutation [42]. ...
Anaplastic thyroid carcinoma (ATC) is the most aggressive thyroid cancer with a median survival of 4–6 months. Identification of mutations contributing to aberrant activation of signaling cascades in ATC may provide novel opportunities for targeted therapy. Thirty-nine ATC samples were studied by next-generation sequencing (NGS) with an established gene panel. High quality readout was obtained in 30/39 ATC. Twenty-eight ATC harbored a mutation in at least one of the studied genes: TP53 (18/30), NF1 (11/30), ALK (6/30), NRAS (4/30), ATRX (3/30), BRAF (2/30), HRAS (2/30), KRAS (1/30). In 17/30 ATC (54 %) mutations were found in two or more genes. Twenty-one of the identified variants are listed in COSMIC as somatic mutations reported in other cancer entities. In three ATC samples no mutations were detected and none of the ATCs was positive for BRAFV600E. The most frequent mutations were found in TP53 (60 %), followed by NF1 (37 %). ALK mutations were detected in 20 % of ATC and were more frequent than RAS or BRAF mutations. ATRX mutations were identified in 10 % of the ATC samples. These sequencing data from 30 ATC samples demonstrate the accumulation of genetic alterations in ATC because in 90 % of samples mutations were already found in the investigated nine genes alone. Mutations were found with high prevalence in established tumor suppressor and oncogenes in ATC, such as TP53 and H/K/NRAS, but also, although less frequent, in genes that may harbor the potential for targeted treatment in a subset of ATC patients, such as ALK and NF1.
... A recent large-cohort, multicenter study identified an association of the BRAF V600E mutation with a higher mortality rate in patients with PTC [4]. However, several other studies have reported no or a partial association of the BRAF mutation with high-risk pathological characteristics [5][6][7]. The association of the BRAF V600E mutation with more aggressive clinicopathological features in patients with PTC thus remains controversial. ...
Background:
The BRAF V600E and telomerase reverse transcriptase (TERT) promoter mutations have been reported in papillary thyroid carcinoma (PTC). The aim of this retrospective cross-sectional study was to add further information regarding the prevalence of the BRAF V600E and TERT promoter mutations in Chinese PTC and their clinicopathological associations.
Methods:
We detected the BRAF V600E mutation and TERT promoter mutations in 455 Chinese PTC patients and analyzed the association of these mutations with several clinicopathological features.
Results:
The BRAF V600E mutation was detected in 343 (75.4%) of 455 cases and was significantly associated with older age (p<0.001) and conventional subtype (p = 0.003). TERT promoter mutations were detected in 19 (4.4%) of 434 PTCs and were associated with older age (p<0.001), larger tumor size (p = 0.024), and advanced TNM stage(p<0.001). Of the 19 patients that were positive for TERT promoter mutations, 18 (94.7%) also harbored the BRAF V600E mutation.
Conclusion:
We determined the prevalence and clinicopathological associations of BRAF V600E and TERT promoter mutations in Chinese PTC patients. TERT promoter mutations but not the BRAF V600E mutation were associated with more advanced TNM stage upon diagnosis.
... Some studies claimed that BRAF V600E mutation was associated with poor clinicopathologic results such as tumor metastasis, recurrence and advanced clinical stages [14][15][16]. On the other hand, others suggested that BRAF V600E mutation had no significant association with clinical stage, age, gender, multicentricity or recurrence [17,18]. This inconsistency may result from different study populations and different study design. ...
Background/aims:
The function of BRAF V600E as a prognostic biomarker continues controversial by reason of conflicting results in the published articles.
Methods:
A systematical literature search for relevant articles was performed in PubMed, Cochrane Library, Google Scholar, Medline and Embase updated to August 5, 2015. The Chi-square test and I2 were employed to examine statistical heterogeneity. Pooled ORs with their corresponding 95% confidence intervals (95%CIs) were calculated to assess the relationship between clinicopathological features and BRAF(V600E) mutation. Subgroup analyses by ethnicity were also performed to explore the potential sources of heterogeneity. Furthermore, publication bias was detected using the funnel plot and all statistical analyses were conducted by the software of R 3.12.
Results:
Of 25,241 cases with PTC, 15,290 (60.6%) were positive for BRAF mutation and 9,951 (39.4%) were tested negative for BRAF mutation. Negative status of BRAF(V600E) mutation negative was significantly associated with gender (OR = 0.90, 95%CI = 0.83-0.97) and concomitant hashimoto thyroiditis (OR = 0.53, 95%CI = 0.43-0.64). By contrast, positive status of BRAF(V600E) mutation was a significant predictor of multifocality (OR = 1.23; 95%CI = 1.14-1.32), extrathyroidal extension (OR = 2.23; 95%CI = 1.90-2.63), TNM stage (OR = 1.67; 95%CI = 1.53-1.81), lymph node metastasis (OR = 1.67; 95%CI = 1.45-1.93), vascular invasion (OR = 1.47; 95%CI = 1.22-1.79) and recurrence/persistence (OR = 2.33; 95%CI = 1.71-3.18). However, there was no significant association between BRAF(V600E) mutation and factors including age > 45 (OR = 0.98; 95%CI = 0.89-1.07), tumor size (OR = 0.84; 95%CI = 0.64-1.09) and distant metastasis (OR = 1.23; 95%CI = 0.67-2.27).
Conclusion:
This meta-analysis confirmed significant associations between BRAF(V600E) mutation and female gender, multifocality, ETE, LNM, TNM stage, concomitant hashimoto thyroiditis, vascular invasion and recurrence/persistence, suggesting the predictive value of BRAF(V600E) mutation for PTC prognosis.
Two-thirds of differentiated thyroid cancer (DTC) patients with distant metastases would be classified as radioactive iodine-refractory (RAIR-DTC), evolving into a poor outcome. Recent advances underlying DTC molecular mechanisms have shifted the therapy focus from the standard approach to targeting specific genetic dysregulations. Lenvatinib and sorafenib are first-line, multitargeted tyrosine kinase inhibitors (TKIs) approved to treat advanced, progressive RAIR-DTC. However, other anti-angiogenic drugs, including single targeted TKIs, are currently being evaluated as alternative or salvage therapy after the failure of first-line TKIs. Combinatorial therapy of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signalling cascade inhibitors has become a highly advocated strategy to improve the low efficiency of the single agent treatment. Recent studies pointed out targetable alternative pathways to overcome the resistance to MAPK and PI3K pathways' inhibitors. Because radioiodine resistance originates in DTC loss of differentiation, redifferentiation therapies are currently being explored for efficacy. The present review will summarize the conventional management of DTC, the first-line and alternative TKIs in RAIR-DTC, and the approaches that seek to overcome the resistance to MAPK and PI3K pathways' inhibitors. We also aim to emphasize the latest achievements in the research of redifferentiation therapy, immunotherapy, and agents targeting gene rearrangements in advanced DTC.
Purpose: This study focuses on the oncologic influence of BRAF V600E mutations in a cohort of Middle Eastern PTC patients treated at a single centre. We test the association of BRAFV600E mutation with papillary thyroid carcinoma at King Hussein Cancer Center.
Methods: Patients with histologically confirmed PTC who underwent surgical treatment between 2006 and 2015 were included in this study. Oncological outcomes, both short and long termed were collected.
Results: A total of 128 patients (68% females) were included in this study with a mean age of 38 years (±13.8). The median follow-up period was 50 months. The BRAF V600E mutation was found in 71% of patients. The tumor size for patients with a negative BRAF V600E mutation were significantly larger in comparison to patients who tested positive for the mutation (3.47 cm versus 2.31 cm, respectively, P = 0.009). The two groups showed similar disease-free survival (DFS) rates; positive = 75% (median 43 months (0-168)) compared to 78% for the negative BRAF V600E mutation (median 38 months (3-142)) (P= 0.162, HR=0.731) Furthermore, both groups showed similar overall survival rates: positive = 94.5% (median 56 months (0-228)) compared to 94.6% for the negative BRAF V600E mutation (median 43 months (3-157)) (P = 0.941, HR= 0.940).
Conclusion: BRAF V600E mutation had no effect on loco-regional recurrence, distant metastasis, overall survival or disease-free survival. These findings may be attributed to geographic variations or reflect that BRAF V600E may only serve as an indicator of poor prognosis in high risk groups.
Introduction BRAF V600E is one of the most common mutations in Papillary Thyroid Cancer (PTC). Its clinical correlation has been extensively studied with contradictory results. The aim of this study is to evaluate the oncological impact of BRAF V600E mutation on a cohort of Middle Eastern PTC patients treated at a single institute.
Methods Patients with histologically confirmed PTC that were treated surgically between 2006 to 2015 were included in the study. Formalin fixed paraffin embedded tumor blocks were sectioned and tested for BRAF V600E mutation. Short- and long-term oncological outcomes were collected.
Results 128 patients (68% females) were included with a mean age of 38 years (±13.8). Median follow-up was 50 months. BRAF V600E mutation was found in 71% of patientsI
The BRAF negative tumors were significantly larger than the BRAF positive (3.47 cm versus 2.31 cm respectively, P = 0.009). All other clinicopathological characteristics were comparable between BRAF V600E mutation positive and negative groups. The two groups showed similar 5-year Disease-free (P= 0.37) and Overall survival rates (P = 0.94).
Conclusion BRAF V600E mutation did not affect loco-reginal recurrence, distant metastasis, overall and disease-free survival. These results support the diversity of BRAF V600E significance among various ethnicities.
CXCL8 is a chemokine secreted by normal and thyroid cancer cells with proven tumor-promoting effects. The presence of BRAFV600E mutation is associated with a more aggressive clinical behavior and increased ability to secrete CXCL8 by papillary-thyroid-cancer cells. Aim of this study was to test the effect of the BRAF-inhibitor (PLX4720) on the basal and TNF-α-induced CXCL8 secretions in BRAFV600E mutated (BCPAP, 8305C, 8505C), in RET/PTC rearranged (TPC-1) thyroid-cancer-cell-lines and in normal-human-thyrocytes (NHT). Cells were incubated with increasing concentrations of PLX4720 alone or in combination with TNF-α for 24-hours. CXCL8 concentrations were measured in the cell supernatants. PLX4720 dose-dependently inhibited the basal and the TNF-α-induced CXCL8 secretions in BCPAP (F: 14.3, p < 0.0001 for basal and F: 12.29 p < 0.0001 for TNF-α), 8305C (F: 407.9 p < 0.0001 for basal and F: 5.76 p < 0.0001 for TNF-α) and 8505C (F:55.24 p < 0.0001 for basal and F: 42.85 p < 0.0001 for TNF-α). No effect was found in TPC-1 (F: 1.8, p = 0.134 for basal; F: 1.6, p = 0.178 for TNF-α). In NHT an inhibitory effect was found only at the highest concentration of PLX4720 (F: 13.13 p < 0.001 for basal and F: 2.5 p < 0.01 for TNF-α). Cell migration assays showed that PLX4720 reduced both basal and CXCL8-induced cell migration in BCPAP, 8305C, 8505C and NHT but not in TPC-1 cells. These results constitutes the first demonstration that PLX4720 is able to inhibit the secretion of CXCL8 in BRAFV600E mutated thyroid cancer cells indicating that, at least some, of the anti-tumor activities of PLX4720 could be exerted through a lowering of CXCL8 in the thyroid-cancer-microenvironment.
The majority of papillary thyroid carcinoma (PTC) cases comprise classic papillary (C-PTC) and follicular variant (FV-PTC) histologic sub-types. Historically, clinical equivalency was assumed, but recent data suggests C-PTC may have poorer outcomes. However, large single-institution series with long-term outcomes of C-PTC and FV-PTC, using modern pathologic criteria for FV-PTC, are needed. Our objective was to compare prevalence and impact of clinicopathologic factors, including BRAF mutation status, on long-term outcomes of C-PTC and FV-PTC. We hypothesized that patients with C-PTC would have higher risk disease features and worse survival outcomes. This retrospective study included 1293 patients treated at a single, US academic institution between 1943 and 2009 with mean follow-up of 8.6 years. All patients underwent either partial or total thyroidectomy and had invasive C-PTC or FV-PTC per modern pathology criteria. Primary study measurements included differences in recurrence-free survival (RFS), disease-specific survival (DSS), and associations with clinicopathologic factors including the BRAF mutation. Compared to FV-PTC, C-PTC was associated with multiple features of high-risk disease (P < 0.05) and significantly reduced RFS and DSS. Survival differences were consistent across univariate, multivariate, and Kaplan Meier analyses. BRAF mutations were more common in C-PTC (P = 0.002). However, on Kaplan Meier analysis, mutational status did not significantly impact RFS or DSS for patients with either histologic sub-type. C-PTC therefore indicates higher-risk disease and predicts for significantly poorer long-term outcomes when compared to FV-PTC. The nature of this difference in outcome is not explained by traditional histopathologic findings, or by the BRAF mutation.
Objective
BRAF mutation is the commonest mutation seen in papillary thyroid cancer (PTC), but its prevalence and clinical significance vary across countries. We aim to evaluate the prevalence and clinico‐pathological correlation of BRAF mutation in PTC patients at our center.
Study Design
Retrospective cohort study of 75 consecutive archival thyroid specimens, whereby BRAF mutation was detected using a polymerase chain reaction (PCR) technique and correlated with clinical and pathological features and outcomes.
Setting
Tertiary university hospital in Singapore.
Participants
75 consecutive histologically proven archival thyroid specimens from patients who underwent thyroidectomy for PTC were accrued for this study.
Main outcome measures
Main outcome is to determine the prevalence of the BRAF mutation in our Southeast Asian population. Secondary aim is to correlate the mutational status with adverse pathological features like histological variants, multifocality, lymphovascular invasion and extrathyroidal extension, clinical features like demographics, TNM stage, recurrence and survival, as well as treatment details like type of surgery performed and radioiodine doses.
Results
BRAF mutation was detected in 56% (42/75) of PTC. All but one BRAF‐mutated PTC had the BRAFV600E mutation. BRAF‐mutated tumors were associated with an advanced T‐stage (p=0.049); and were more likely to have a central neck dissection (p=0.036). There was no significant correlation between BRAF mutation status and clinical outcomes.
Conclusion
The prevalence of BRAF mutation is 56%. BRAF‐mutation positive tumors were associated with locally‐advanced disease, but not poorer survival.
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Mutation in BRAF is well known for its oncogenic effect. Point mutations in V599 are particularly found oncogenic and considered important for therapeutic purpose. Along with wild type, other V599 mutated BRAF variants viz V599E, V599D and V599R are also reported and crystals of former two with inhibitor (BAY43- 9006) is further detailed. Both the BRAF forms showed particularly similar interaction patterns with BAY43-9006 and 599th residue did not found anyway involved in the interactions. Upon BAY43-9006 binding, kinase domains of both the forms were further found adopting essentially the identical conformations. Contrary to this, BAY43-9006 showed varied activity profile in case of wild and V599E variant of BRAF protein. Furthermore, MMGBSA binding energy results for all the four BRAF variants, further revealed the importance of 599th residue. In-depth analysis viz molecular dynamics, residue correlation studies and residue interaction network (RIN) analysis were investigated, providing a deep insight of 599th residue and its impact on overall dynamics of BRAF protein. Our findings revealed that the mutated residue at 599th position not only changed the BAY43-9006–BRAF binding behaviour but also produced a massive impact on the overall dynamic behaviour of the protein. The insights obtained herein could be of great relevance while designing new BRAF inhibitors towards getting ideal activity against all the BRAF forms.
Background:
BRAFV600E (c.1799T>A) somatic mutation evaluation in fine needle aspiration biopsies (FNAB) is a powerful diagnostic tool in the settings of papillary thyroid cancer (PTC). However, its prognostic value is still a matter of great debate and has been addressed mostly in retrospective studies.
Objectives:
To evaluate whether the somatic BRAFV600E mutation, assessed by direct sequencing in FNAB material of thyroid nodules, may correlate with disease persistence in PTC patients.
Study design:
We conducted a prospective cohort study investigating 160 PTC patients previously assessed for the somatic BRAFV600E mutation, and submitted to total thyroidectomy, with a follow-up of 2-10 years. Patients were matched according to somatic BRAFV600E mutation (80 BRAF+ and 80 BRAF- patients) and to the presence (LN+, 40 patients each group) or absence (LN, 40 patients each group) of neck lymphnode metastases. Disease persistence was considered according to basal or TSH-stimulated Thyroglobulin (TG) levels, anti-TG antibodies, neck ultrasound, CT scan where applicable and whole body scan after radioiodine ablation treatment (RAI).
Results:
The presence of the somatic BRAFV600E mutation did not influence the indication for RAI. None of the enrolled patients showed disease recurrence or died due to disease-related causes. During follow-up, disease persistence did not correlate with the presence of somatic BRAFV600E mutation both in patients submitted to RAI nor in those treated more conservatively.
Conclusions:
The somatic BRAFV600E mutation does not associate with a worse prognosis in low risk PTC and, in our settings, may not be considered an independent risk factor for disease persistence.
Introduction
The incidence of papillary thyroid cancer is increasing faster than any other cancer in young patients. The purpose of this review is to discuss the most recent determinants of risk of recurrence and compromised outcomes in this population.
Areas covered
This review discusses the most updated data on patient age, including children and young adults, extent of disease and subsequent dynamic staging over time, molecular markers for disease aggressiveness, adequacy of surgical resection and surgeon volume, and novel therapies for advanced non-resectable disease as predictors of patient outcomes.
Expert Commentary
Young patients enjoy excellent outcomes, with long-term survivorship, but face higher risks of short-term complications and disease recurrence. Thoughtful evaluation of the extent of disease, tumor features associated with more aggressive behavior, the presence of locoregional or distant metastases, and an understanding of molecular changes in their tumors are important areas of consideration. High-volume surgeons should work collaboratively with endocrinologists, radiologists, and pathologists specializing in thyroid cancer to help patients achieve excellent outcomes. Emerging data challenging the status quo regarding the relative importance of patient age, tumor features, and dynamic risk-adjustment for overall prognosis of these patients will likely impact future care and staging systems.
At the time of conception, the human organism is a single cell zygote. During the course of development into an adult, this cell expands into a complex mass of approximately 100 trillion cells, with an enormous variety of shapes, sizes, and functions. Normal tissue growth and development require prolific cell division, exquisitely regulated cell differentiation, and appropriately timed cell death or apoptosis. Neoplastic transformation of tissue generally occurs when abnormal regulatory mechanisms promote excessive cell division, impaired cell differentiation, and/or failure of apoptosis. In most tumor types, this aberrant control originates at the genetic level. Intensive study of these regulatory mechanisms has led to significant progress in our ability to diagnose, predict biological behavior, and understand the basic molecular pathophysiology of thyroid neoplasms. The upcoming sections explore the major advances in the study of thyroid oncogenes and tumor suppressor genes and address the clinical utility of these discoveries.
The increased prevalence of BRAF mutations in thyroid carcinoma and primary cutaneous melanoma (PCM) hint that dysregulation of BRAF might contribute to the noted association between PCM and thyroid carcinoma. A recent study evaluating the rate of BRAFV600E mutations among patients who had been diagnosed with primary papillary thyroid carcinoma (PTC) and PCM showed that patients with either PCM or PTC were at an increased risk of developing the other as a second primary malignant neoplasm. Furthermore, the authors noted that samples from patients suffering from both malignancies exhibited a higher rate of incidence of the BRAFV600E mutation, compared with patients not suffering from both malignancies. These studies support the hypothesis that the pathogenesis of these 2 malignancies might share a conserved molecular pattern associated with dysregulation of the BRAF protein. One mechanism through which BRAF might contribute to PCM and thyroid carcinoma progression is through induction of epithelial-mesenchymal transition (EMT). Specifically, the Snail/E-cadherin axis has been demonstrated as a pathway dysregulated by BRAF, leading to EMT in both malignancies. Our analysis focuses on the results of these recent investigations, and through a review of select molecules relevant to EMT, looks to provide a context by which to better understand the relevance and role of stromal-parenchymal signaling and the BRAF mutation in the pathogenesis of PTC and PCM.
Background:
The BRAF (V600E) mutation is a recognised molecular marker in papillary thyroid cancer (PTC), reported incidence from 30 to 80 %. BRAF(V600E) aberrantly activates the MAPK pathway, a central regulator of cell growth and proliferation. Previous studies have reported conflicting data regarding the impact of BRAF(V600E) on clinicopathological features of PTC. The study aims to determine whether BRAF(V600E) is useful as a prognostic biomarker in PTC.
Methods:
A cohort study of patients undergoing surgery for PTC was undertaken. The primary outcome measure was disease-free survival. Secondary outcome measures were tumour size, nodal positivity and radioactive iodine ablation rate. All cases were re-examined to confirm PTC. Immunohistochemistry for BRAF(V600E) was performed on tissue microarrays. A single endocrine pathologist, blinded to clinicopathological data, interpreted staining.
Results:
496 patients with PTC were included, and 309 (62 %) were BRAF(V600E) positive. Tumour size was similar for BRAF(V600E)-positive and -negative tumours (21.3 vs. 23.2 mm, p = 0.23). BRAF(V600E)-positive patients were significantly older at first operation (mean age 45 versus 49 years, p = 0.003). BRAF(V600E)-positive PTCs had a higher rate of disease recurrence (12.9 vs. 5.6 %, p = 0.004), lymph node metastasis (44 vs. 29.4 %, p = 0.004) and extra-thyroidal extension (44 vs. 22 %, p < 0.001). Five-year disease-free survival was 89.6 % for BRAF(V600E) positive and 96.3 % for negative tumours, p < 0.001. There was no difference between groups for vascular invasion or multifocality. The mean follow-up was 57 months for both groups.
Conclusion:
BRAF(V600E) in PTC predicts an increased risk of lymph node metastasis, extra-thyroidal extension and reduced disease-free survival. It is an additional useful prognostic biomarker.
Background: The risk factors determining the aggressiveness of papillary thyroid microcarcinoma (PTMC) are not well known. Aim: To determine if tumor size, along with other features of the tumor, influences its prognosis. Patients and Methods: We analyzed the medical records of 147 patients (age range 16-92 years, 93% women) at the Clinical Hospital of University of Chile who underwent thyroid surgery and in whom at least one focus of PTMC was found. We determined the association between different clinical characteristics and the presence of capsular invasion,. lymph nodal extension or recurrence. Results: A tumor size over 5 mm, a follicular subtype and being aged more than 45 years, were significantly associated with the presence of capsular invasion. The latter two variables were protective. In the multivariate analysis, only a tumor size over 5 mm was significantly associated with thyroid capsule involvement. Conclusions: A tumor size over 5 mm is associated with capsular invasion in PTMC.
Context:
Individualized management, incorporating papillary thyroid cancer (PTC) variant-specific risk, is conceivably a useful treatment strategy for PTC, which awaits comprehensive data demonstrating differential risks of PTC variants to support.
Objective:
To establish the differential clinicopathological risk of major PTC variants-conventional PTC (CPTC), follicular-variant PTC (FVPTC), and tall-cell PTC (TCPTC).
Methods:
Retrospective study of clinicopathological outcomes of 6,282 PTC patients (4,799 females and 1,483 males) from 26 centers and The Cancer Genome Atlas in 14 countries with a median age of 44 years (interquartile range [IQR], 33-56) and median follow-up time of 37 months (IQR 15-82).
Results:
The cohort consisted of 4,702 (74.8%) CPTC, 1,126 (17.9%) FVPTC, and 239 (3.8%) TCPTC. The prevalence of high-risk parameters was significantly different among the three variants, including extrathyroidal invasion, lymph node metastasis, stages III/IV, disease recurrence, mortality and the use (need) of radioiodine treatment (all P < 0.001), being highest in TCPTC, lowest in FVPTC, and intermediate in CPTC, following an order of TCPTC>CPTC≫FVPTC. Recurrence and mortality in TCPTC, CPTC, and FVPTC were 27.3% and 6.7%, 16.1% and 2.5%, and 9.1% and 0.6%, corresponding to events per 1000 person-years (95% confidence interval-CI) of 92.47 (64.66-132.26) and 24.61 (12.31-49.21), 34.46 (30.71-38.66) and 5.87 (4.37-7.88), and 24.73 (18.34-33.35) and 1.68 (0.54-5.21), respectively. Mortality hazard ratios of CPTC and TCPTC over FVPTC were 3.44 (95% CI 1.07-11.11) and 14.96 (95% CI 3.93-56.89), respectively. Kaplan-Meier survival analyses showed the best prognosis in FVPTC, worst in TCPTC, and intermediate in CPTC in disease recurrence-free probability and disease-specific patient survival. This was particularly the case in patients ≥ 45 years old.
Conclusion:
This large multicenter study demonstrates differential prognostic risks of the three major PTC variants and establishes a unique risk order of TCPTC > CPTC ≫ FVPTC, providing important clinical implications for specific variant-based management of PTC.
We have recently reported the activation of a new oncogene in human papillary thyroid carcinomas. This oncogene, papillary thyroid carcinoma (PTC), is a novel rearranged version of the ret tyrosine-kinase protooncogene. Thyroid neoplasms include a broad spectrum of malignant tumors, ranging from well-differentiated tumors to undifferentiated anaplastic carcinomas. To determine the frequency of ret oncogene activation, we analyzed 286 cases of human thyroid tumors of diverse histologic types. We found the presence of an activated form of the ret oncogene in 33 (19%) of 177 papillary carcinomas. By contrast, none of the other 109 thyroid tumors, which included 37 follicular, 15 anaplastic, and 18 medullary carcinomas, and 34 benign lesions, showed ret activation.
The papillary carcinoma family (PCF) of thyroid tumors includes a wide variety of neoplastic entities regarded as well-differentiated, poorly differentiated, and undifferentiated papillary thyroid carcinomas. Recent studies have established the presence of alternative oncogenic rearrangements of the RET and NTRK1 genes in a consistent fraction (< or = 50%) of papillary thyroid tumors. RET oncogenic rearrangements are also very frequent (approximately 60%) in Chernobyl radiation-associated papillary thyroid neoplasias, which show an increased aggressiveness in terms of pathological stage at disease onset. These observations prompted us to study the relationship between the presence or absence of RET and NTRK1 oncogenes and the clinicopathological features (age, sex, histopathology, and pTNMC2 staging) of 76 consecutive, non-radiation-related tumors of the PCF. As previously reported, statistical univariate analysis revealed a correlation between the combination of RET and NTRK1 (RET/NTRK1) positivity and young age of patients at diagnosis. In addition, a significant association was found between RET/NTRK1 positivity and locally advanced stage of disease at presentation (pT4: P < 0.015). The multivariate analysis confirmed that RET/NTRK1 activation parallels an unfavorable disease presentation, which may correlate with a less favorable disease outcome. Furthermore, within the PCF, the frequency of RET/NTRK1 positivity was not influenced by the different neoplastic subtypes or the tumor versus degree of differentiation.
Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS RAF MEK ERK MAP kinase pathway mediates cellular responses to growth signals. RAS is mutated to an oncogenic form in about 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS. Here we report BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V599E mutation. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma.
Mutations of the BRAF protein serine/threonine kinase gene have recently been identified in a variety of human cancers, most notably melanomas. We sought to determine the frequency of BRAF mutations in human lung cancer pathogenesis. Analysis of BRAF sequence from 127 primary human lung adenocarcinomas revealed mutations in two tumor specimens, one in exon 11 (G465V), and a second in exon 15 (L596R). These specimens belong to the same adenocarcinoma subgroup as defined by clustering of gene expression data. BRAF may provide a target for anticancer chemotherapy in a subset of lung adenocarcinoma patients.
Thyroid papillary cancers (PTCs) are associated with activating mutations of genes coding for RET or TRK tyrosine kinase receptors, as well as of RAS genes. Activating mutations of BRAF were reported recently in most melanomas and a small proportion of colorectal tumors. Here we show that a somatic mutation of BRAF, V599E, is the most common genetic change in PTCs (28 of 78; 35.8%). BRAF(V599E) mutations were unique to PTCs, and not found in any of the other types of differentiated follicular neoplasms arising from the same cell type (0 of 46). Moreover, there was no overlap between PTC with RET/PTC, BRAF, or RAS mutations, which altogether were present in 66% of cases. The lack of concordance for these mutations was highly unlikely to be a chance occurrence. Because these signaling proteins function along the same pathway in thyroid cells, this represents a unique paradigm of human tumorigenesis through mutation of three signaling effectors lying in tandem.
The BRAF gene has been found to be activated by mutation in human cancers, predominantly in malignant melanoma. We tested
476 primary tumors, including 214 lung, 126 head and neck, 54 thyroid, 27 bladder, 38 cervical, and 17 prostate cancers, for
the BRAF T1796A mutation by polymerase chain reaction (PCR)–restriction enzyme analysis of BRAF exon 15. In 24 (69%) of the
35 papillary thyroid carcinomas examined, we found a missense thymine (T)→adenine (A) transversion at nucleotide 1796 in the
BRAF gene (T1796A). The T1796A mutation was detected in four lung cancers and in six head and neck cancers but not in bladder,
cervical, or prostate cancers. Our data suggest that activating BRAF mutations may be an important event in the development
of papillary thyroid cancer.
Rearrangement of RET proto-oncogene is the major event in the etiopathogenesis of papillary thyroid carcinoma (PTC). We report a high prevalence of BRAF(V599E) mutation in sporadic PTC and in PTC-derived cell lines. The BRAF(V599E) mutation was detected in 23 of 50 PTC (46%) and in three of four PTC-derived cell lines. The prevalence of the BRAF(V599E) mutation in PTC is the highest reported to date in human carcinomas, being only exceeded by melanoma. PTC with RET/PTC rearrangement as well as the TPC-1 cell line (the only one harboring RET/PTC rearrangement) did not show the BRAF(V599E) mutation. BRAF(V599E) mutation was not detected in any of 23 nodular goiters, 51 follicular adenomas and 18 follicular carcinomas. A distinct mutation in BRAF (codon K600E) was detected in a follicular adenoma. Activating mutations in RAS genes were detected in 15% of FA, 33% of FTC and 7% of PTC. BRAF(V599E) mutation did not coexist with alterations in any of the RAS genes in any of the tumors. These results suggest that BRAF(V599E) mutation is frequent in the etiopathogenesis of PTC. The BRAF(V599E) mutation appears to be an alternative event to RET/PTC rearrangement rather than to RAS mutations, which are rare in PTC. BRAF(V599E) may represent an alternative pathway to oncogenic MAPK activation in PTCs without RET/PTC activation.
The RAS-RAF-MEK-ERK-MAP kinase pathway mediates the cellular response to extracellular signals that regulate cell proliferation, differentiation, and apoptosis. Mutation of the RAS proto-oncogene occurs in various thyroid neoplasms such as papillary thyroid carcinomas (PTCs), follicular thyroid adenomas and carcinomas. A second genetic alteration frequently involved in PTC is RET/PTC rearrangements. Recent studies have shown that BRAF, which is a downstream signaling molecule of RET and RAS, is frequently mutated in melanomas. This study tests whether BRAF is also mutated in thyroid tumors and cell lines. We analyzed BRAF gene mutation at codon 599 in thyroid tumors using mutant-allele-specific PCR and in 10 thyroid tumor cell lines by DNA sequencing of the PCR-amplified exon 15. We found that BRAF was mutated in 8 of 10 thyroid tumor cell lines, including 2 of 2 papillary carcinoma cell lines, 4 of 5 anaplastic carcinoma cell lines, 1 of 2 follicular carcinoma cell lines, and 1 follicular adenoma cell line. BRAF mutation at codon 599 was detected in 21 of 56 PTC (38%) but not in 18 follicular adenomas and 6 goiters. BRAF mutation occurred in PTC at a significantly higher frequency in male patients than in female patients. To test whether BRAF mutation may cooperate with RET/PTC rearrangements in the oncogenesis of PTC, we tested whether BRAF-mutated PTCs were also positive for RET/PTC rearrangements. Immunohistochemical staining was conducted to evaluate RET/PTC rearrangements by using two different anti-RET antibodies. Surprisingly, we found that a large number of BRAF-mutated PTCs (8 of 21) also expressed RET, indicating that the RET proto-oncogene is rearranged in these BRAF-mutated PTCs. These observations suggest that mutated BRAF gene may cooperate with RET/PTC to induce the oncogenesis of PTC.
BRAF is a serine/threonine kinase that receives a mitogenic signal from RAS and transmits it to the MAP kinase pathway. Recent studies have reported that mutations of the BRAF gene were detected with varying frequencies in several cancers, notably more than 60% in melanoma. We analysed mutations of BRAF and RAS genes in 100 cases of thyroid carcinoma to investigate genetic aberrations in the RAS/RAF/MEK/MAP kinase pathway. BRAF mutations were detected exclusively in papillary carcinomas (40 in 76 cases: 53%), and were exclusively V599E, a mutation frequently observed in other carcinomas. NRAS mutation was observed in six cases (6%), all in histological types other than papillary carcinoma, and was exclusively Q61R. No mutations were found in KRAS or HRAS. Our results suggest that BRAF mutations may play a critical role in the carcinogenesis of papillary carcinoma of the thyroid.
Ras proteins control signaling pathways that are key regulators of several aspects of normal cell growth and malignant transformation. BRAF, which encodes a RAF family member in the downstream pathway of RAS, is somatically mutated in a number of human cancers. The activating mutation of BRAF is known to play a role in tumor development. As there have been no data on the BRAF mutation in stomach cancer, we analysed the genomic DNAs from 319 stomach carcinomas for the detection of somatic mutations of BRAF. Overall, we detected BRAF mutations in seven stomach carcinomas (2.2%). Five of the seven BRAF mutations involved Val 599, the previously identified hotspot, but the substituted amino acid (V599 M) was different from the most common BRAF mutation (V599E). The remaining two mutations involved a conserved amino acid (D593G). One tumor had both BRAF and KRAS mutations. This is the first report on BRAF mutation in stomach cancer, and the data indicate that BRAF is occasionally mutated in stomach cancer, and suggest that alterations of RAS pathway both by RAS and BRAF mutations contribute to the pathogenesis of stomach cancer.
Activating point mutations of the BRAF gene have been recently reported in papillary thyroid carcinomas. In this study, we analyzed 320 thyroid tumors and six anaplastic carcinoma cell lines and detected BRAF mutations in 45 (38%) papillary carcinomas, two (13%) poorly-differentiated carcinomas, three (10%) anaplastic carcinomas, and five (83%) thyroid anaplastic carcinoma cell lines but not in follicular, Hürthle cell, and medullary carcinomas, follicular and Hürthle cell adenomas, or benign hyperplastic nodules. All mutations involved a T-->A transversion at nucleotide 1796. In papillary carcinomas, BRAF mutations were associated with older age, classic papillary carcinoma or tall cell variant histology, extrathyroidal extension, and more frequent presentation at stages III and IV. All BRAF-positive poorly differentiated and anaplastic carcinomas contained areas of preexisting papillary carcinoma, and mutation was present in both the well-differentiated and dedifferentiated components. These data indicate that BRAF mutations are restricted to papillary carcinomas and poorly differentiated and anaplastic carcinomas arising from papillary carcinomas. They are associated with distinct phenotypical and biological properties of papillary carcinomas and may participate in progression to poorly differentiated and anaplastic carcinomas.
Ocogenic activation of the BRAF gene has been demonstrated to be involved in the pathogenesis of malignant melanoma (MM). In this study, we investigated the contribution of BRAF to melanoma susceptibility, also making a comparison with frequency of CDKN2A germline mutations in MM patients from different areas in Italy.
sing a combination of denaturing high-performance liquid chromatography analysis and automated sequencing on genomic DNA from peripheral blood or tumor tissue samples, 569 MM patients (211 from northern Italy and 358 from southern Italy) were screened for BRAF mutations.
Three BRAF germline sequence variants (M116R, V599E, and G608H) were identified in four (0.7%) of 569 MM patients. The most common BRAF mutation, V599E, was detected in one germline DNA sample only; M116R and G608H were newly described mutations. A high frequency (59%) of BRAF mutations was instead observed in tumor samples from patients also undergoing germline DNA analysis; at the somatic level, substitution of valine 599 was found to account for the majority (88%) of BRAF mutations. We then estimated the germline mutation rates in BRAF and CDKN2A among 358 consecutively collected patient samples originating in southern Italy; a low (2.5%) or very low (0.29%) prevalence of CDKN2A and BRAF mutations, respectively, was detected.
utation analysis of either blood DNA from a large collection of MM patients or matched MM tissues from a subset of such patients revealed that BRAF is somatically mutated and does not play a major role in melanoma susceptibility. The present study further suggests that patient origin may account for different mutation rates in candidate genes.
A high prevalence of activating mutation of the B type Raf kinase (BRAF) gene was recently reported in papillary thyroid cancer (PTC). However, the frequency of this mutation in several other types of thyroid neoplasms was not thoroughly investigated. In the present study, in addition to PTC, we evaluated various thyroid tumor types for the most common BRAF T1796A mutation by direct genomic DNA sequencing. We found a high and similar frequency (45%) of the BRAF T1796A mutation in two geographically distinct PTC patient populations: one composed of sporadic cases from North America, and the other from Kiev, Ukraine, that included individuals who were exposed to the Chernobyl nuclear accident. In contrast, we found BRAF mutation in only 20% of anaplastic thyroid cancers and no mutation in medullary thyroid cancers and benign thyroid hyperplasia. We also confirmed previous reports that the BRAF T1796A mutation did not occur in benign thyroid adenomas and follicular thyroid cancers. Specific analysis of the Ukraine patients with confirmed history of radiation exposure failed to show a higher incidence of BRAF mutation. Our results suggest that frequent occurrence of BRAF mutation is inherently associated with PTC, irrespective of geographic origin, and is apparently not a radiation-susceptible mutation. The lack or low prevalence of BRAF mutation in other thyroid neoplasms is consistent with the notion that other previously defined genetic alterations on the same signaling pathway are sufficient to cause tumorigenesis in most thyroid neoplasms.
Activating mutations in the BRAF kinase gene have recently been reported in human cancers. The aim of the present study was to determine the frequency of BRAF mutations in thyroid cancer and their correlation with clinicopathological parameters. We analyzed exons 11 and 15 of BRAF gene in six human thyroid cancer cell lines and 207 paraffin-embedded thyroid tumor tissues. A missense mutation was found at T1796A (V599E) in exon 15 in four of the six cell lines and 51 of 207 thyroid tumors (24.6%; 0 of 20 follicular adenoma, 0 of 11 follicular carcinoma, 49 of 170 papillary carcinomas, and 2 of 6 undifferentiated carcinomas). Activation of MAPK kinase-MAPK pathway was observed in cell lines harboring BRAF mutation. BRAF mutation-associated enhanced cell growth was suppressed by MAPK kinase inhibitor, U0126. Examination of 126 patients with papillary thyroid cancer showed that BRAF mutation correlated significantly with distant metastasis (P = 0.033) and clinical stage (P = 0.049). Our results indicate that activating mutation of BRAF gene could be a potentially useful marker of prognosis of patients with advanced thyroid cancers.
The mitogen-activated protein kinase pathway is thought to be essential in cellular growth and differentiation. Here we report the discovery of a highly potent and selective inhibitor of the upstream kinase MEK that is orally active. Tumor growth was inhibited as much as 80% in mice with colon carcinomas of both mouse and human origin after treatment with this inhibitor. Efficacy was achieved with a wide range of doses with no signs of toxicity, and correlated with a reduction in the levels of activated mitogen-activated protein kinase in excised tumors. These data indicate that MEK inhibitors represent a promising, noncytotoxic approach to the clinical management of colon cancer.
Since the discovery of the role of ras oncogenes in tumorigenesis, we have witnessed an explosion of research in the signal transduction area. In the quest to understand how Ras transmits extracellular growth signals, the MAP kinase (MAPK) pathway has emerged as the crucial route between membrane-bound Ras and the nucleus. The MAPK pathway encompasses a cascade of phosphorylation events involving three key kinases, namely Raf, MEK (MAP kinase kinase) and ERK (MAP kinase). This kinase cascade presents novel opportunities for the development of new cancer therapies designed to be less toxic than conventional chemotherapeutic drugs. Furthermore, as a signal transduction-based approach to cancer treatment, inhibition of any one of these targets has the potential for translational pharmacodynamic evaluation of target suppression. The rationale for targeting the MAP kinase pathway will be reviewed here along with a discussion of various pharmacological approaches and the promise they hold for a new generation of anticancer drugs.
Mutations in the BRAF gene have recently been detected in a wide range of neoplastic lesions with a particularly high prevalence in melanoma and papillary thyroid carcinoma (PTC). The hot-spot mutation BRAF(V599E) is frequently detected in PTC (36-69%), in contrast to its absence in other benign or malignant thyroid lesions. In order to unravel whether there is any association between the occurrence of the BRAF mutation and the histological pattern of PTC, in this study a previous series of 50 PTCs was extended to 134 cases, including ten cases of PTC-related entities-hyalinizing trabecular tumour (HTT) and mucoepidermoid carcinoma (MEC). Using PCR/SSCP and sequencing, the BRAF(V599E) mutation was detected in 45 of the 124 PTCs (36%). No mutations were detected in any case of HTT and MEC. BRAF(V599E) was present in 75% of Warthin-like PTCs and 53% of conventional PTCs, whereas no BRAF(V599E) mutations were detected in any of the 32 cases of the follicular variant of PTC. BRAF(V599E) was also detected in 6 of 11 cases of the oncocytic variant of PTC that displayed a papillary or mixed follicular-papillary growth pattern and in none of the four oncocytic PTCs with a follicular growth pattern. A distinct mutation in BRAF (codon K600E) was detected in three cases of the follicular variant of PTC. This study has confirmed the high prevalence of BRAF(V599E) in PTC and has shown that the mutation is almost exclusively seen in PTC with a papillary or mixed follicular-papillary growth pattern, regardless of the cytological features of the neoplastic cells. The results support the existence of an oncocytic variant of PTC that should be separated from the oncocytic variant of follicular carcinoma and suggest that the follicular variant of PTC may be genetically different from conventional PTC.
Over 30 mutations of the B-RAF gene associated with human cancers have been identified, the majority of which are located within the kinase domain. Here we show that of 22 B-RAF mutants analyzed, 18 have elevated kinase activity and signal to ERK in vivo. Surprisingly, three mutants have reduced kinase activity towards MEK in vitro but, by activating C-RAF in vivo, signal to ERK in cells. The structures of wild type and oncogenic V599EB-RAF kinase domains in complex with the RAF inhibitor BAY43-9006 show that the activation segment is held in an inactive conformation by association with the P loop. The clustering of most mutations to these two regions suggests that disruption of this interaction converts B-RAF into its active conformation. The high activity mutants signal to ERK by directly phosphorylating MEK, whereas the impaired activity mutants stimulate MEK by activating endogenous C-RAF, possibly via an allosteric or transphosphorylation mechanism.
Activation of the RAS/RAF/extracellular signal-regulated kinase-mitogen-activated protein kinase/extracellular signal-regulated kinase/mitogen-activated protein kinase pathway by RAS mutations is commonly found in human cancers. Recently, we reported that mutation of BRAF provides an alternative route for activation of this signaling pathway and can be found in melanomas, colorectal cancers, and ovarian tumors. Here we perform an extensive characterization of BRAF mutations in a large series of colorectal tumors in various stages of neoplastic transformation. BRAF mutations were found in 11 of 215 (5.1%) colorectal adenocarcinomas, 3 of 108 (2.8%) sporadic adenomas, 1 of 63 (1.6%) adenomas from familial adenomatous polyposis (FAP) patients, and 1 of 3 (33%) hyperplastic polyps. KRAS mutations were detected in 34% of carcinomas, 31% of sporadic adenomas, 9% of FAP adenomas, and no hyperplastic polyps. Eight of 16 BRAF mutations were V599E, the previously described hotspot, and none of these was associated with a KRAS mutation in the same lesion. The remaining eight mutations involve other conserved amino acids in the kinase domain, and 62.5% have a KRAS mutation in the same tumor. Our data suggest that BRAF mutations are, to some extent, biologically similar to RAS mutations in colorectal cancer because both occur at approximately the same stage of the adenoma-carcinoma sequence, both are associated with villous morphology, and both are less common in adenomas from FAP cases. By contrast, colorectal adenocarcinomas with BRAF mutations are associated with early Dukes' tumor stages (P = 0.006) and no such relationship was observed for KRAS mutations. The presence in some colorectal neoplasms of mutations in both BRAF and KRAS suggests that modulation of the RAS-RAF-extracellular signal-regulated kinase-mitogen-activated protein kinase/extracellular signal-regulated kinase/mitogen-activated protein kinase signaling pathway may occur by mutation of multiple components.
Genes of the RAF family, which mediate cellular responses to growth signals, encode kinases that are regulated by RAS and participate in the RAS/RAF/MEK/ERK/MAP-kinase pathway. Activating mutations in BRAF have recently been identified in melanomas, colorectal cancers, and thyroid and ovarian tumours. In the present study, an extensive characterization of BRAF and KRAS mutations has been performed in 264 epithelial and non-epithelial ovarian neoplasms. The epithelial tumours ranged from adenomas and borderline neoplasms to invasive carcinomas including serous, mucinous, clear cell, and endometrioid lesions. It is shown that BRAF mutations in ovarian tumours occur exclusively in low-grade serous neoplasms (33 of 91, 36%); these included serous borderline tumours (typical and micropapillary variants), an invasive micropapillary carcinoma and a psammocarcinoma. KRAS mutations were identified in 26 of 91 (29.5%) low-grade serous tumours, 7 of 49 (12%) high-grade serous carcinomas, 2 of 6 mucinous adenomas, 22 of 28 mucinous borderline tumours, and 10 of 18 mucinous carcinomas. Of note, two serous borderline tumours were found to harbour both BRAF and KRAS mutations. The finding that at least 60% of serous borderline tumours harbour mutations in two members of the ERK-MAP-kinase pathway (BRAF 36%, KRAS 30%) compared with 12% of high-grade serous carcinomas (BRAF 0%, KRAS 12%) indicates that the majority of serous borderline tumours do not progress to serous carcinomas. Furthermore, no BRAF mutations were detected in the other 173 ovarian tumours in this study.
TNM classification of malignant tumours
American Joint Committee on Cancer. (2002) TNM classification of
malignant tumours. In: AJCC Cancer Staging Handbook, 6th edn (eds
F. L. Greene & others), pp. 89 -98. Springer-Verlag, New York.