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| ORIGINAL ARTICLE |
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| Year : 2017 | Volume
: 54
| Issue : 1 | Page : 372-378 |
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Role and relevance of BRAF mutations in risk stratifying patients of papillary thyroid cancers along with a review of literature
A Krishnamurthy1, V Ramshankar2, K Murherkar3, S Vidyarani4, GC Raghunandhan5, A Das5, PB Desai1, K Albert6
1 Department of Surgical Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
2 Department of Preventive Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
3 Division of Pathology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
4 Centre for Oral Cancer Prevention Awareness and Research, Sree Balaji Dental College and Hospital, Bharat University, Chennai, Tamil Nadu, India
5 Division of Surgical Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
6 Division of Preventive Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
| Date of Web Publication | 1-Dec-2017 |
Correspondence Address:
Dr. A Krishnamurthy
Department of Surgical Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/ijc.IJC_182_17
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.
Keywords: B-type Raf kinase V600E mutation, cancer recurrence, differentiated thyroid cancer, papillary thyroid cancers, risk stratification
How to cite this article:
Krishnamurthy A, Ramshankar V, Murherkar K, Vidyarani S, Raghunandhan G C, Das A, Desai P B, Albert K. Role and relevance of BRAF mutations in risk stratifying patients of papillary thyroid cancers along with a review of literature. Indian J Cancer 2017;54:372-8 |
How to cite this URL:
Krishnamurthy A, Ramshankar V, Murherkar K, Vidyarani S, Raghunandhan G C, Das A, Desai P B, Albert K. Role and relevance of BRAF mutations in risk stratifying patients of papillary thyroid cancers along with a review of literature. Indian J Cancer [serial online] 2017 [cited 2022 Mar 5];54:372-8. Available from: https://www.indianjcancer.com/text.asp?2017/54/1/372/219557 |
| » Introduction | |  |
Well-differentiated thyroid cancers have become one of the fastest growing malignancies in the world including in India.[1],[2],[3],[4],[5] The incidence in India as per the GLOBOCAN data is 13,801 new cases per 100,000. Thyroid cancers are rapidly increasing with a projected prevalence of 55,539 cases in 2017. The major histological types of thyroid cancers are papillary thyroid cancer (PTC), follicular thyroid cancer, medullary thyroid cancer, and anaplastic thyroid cancer. PTC includes a spectrum histological subtypes differing markedly in biological behavior. The conventional and follicular variants account for around 86%–90% of all PTCs. Considerable progress has been made in understanding the molecular mechanisms underpinning the well-differentiated thyroid cancers over the past two decades. This progress is best represented by the elucidation of the key signaling pathways, namely, mitogen-activated pathway kinase (MAPK) pathway and PI3K pathway.[1] A great majority of the PTCs are slow-growing tumors with a favorable survival rate.[6] However, there are certain clinicopathological factors that denote poor prognosis such as increasing age, extrathyroidal spread (ETS), neck node metastasis, and distant metastasis.[6] Incidentally, many studies have suggested that some of the above adverse clinicopathological factors have been associated with the presence of B-type Raf kinase (BRAF) V600E mutations. Further, given the specificity of BRAF V600E mutations within papillary thyroid cancers, it seems logical to study the mutations in the perspective of diagnosis and prognosis of PTCs. This aspect incidentally has been a topic of considerable debate.[7] We have attempted to assess the prevalence of BRAF V600E mutations in our cohort of well-differentiated thyroid cancers and have correlated the same with the clinicopathological features and survival outcomes in patients with conventional PTCs.
| » Materials and Methods | | |
This is a retrospective study done in a cohort of well-differentiated thyroid cancer patients treated at a tertiary cancer in Chennai, South India, between the years 2005 and 2006. This study, approved by the Institutional Ethical Committee was carried out in 79 paraffin blocks of patients that were histologically confirmed to be well-differentiated thyroid cancers. Every sample was verified for representation of the tumor in the postsurgical histopathology with corresponding hematoxylin and eosin staining before including in the study. DNA was isolated from representative formalin-fixed paraffin-embedded (FFPE) cancer tissues and was used for quantitative polymerase chain reaction (qPCR) as described. The clinicopathological characteristics were retrieved from patient case records. The statistical methods included the correlation of the BRAF V600E positivity with the clinicopathological variables and the survival outcomes.
Molecular testing for B-type Raf kinase status by quantitative polymerase chain reaction
DNA was isolated from the FFPE tumor tissue using high pure FFPE tissue DNA isolation kit (Roche Diagnostics GmBH, Mannheim, Germany). BRAF V600E gene mutation analysis was done using BRAF V600E mutation detection kit (Helini India Pvt. Ltd.) using real-time PCR. The test uses allele-specific probes to identify the presence or absence of mutations V600E (Val600Glu), V600K (Val600Lys), V600D (Val600Asp), V600R (Val600Arg), and V600M (Val600Met) found in codon 600 of BRAF gene by real-time PCR (ABI 7500, Applied Biosystems) with a detection sensitivity of 1% mutant in the background of wild-type genomic DNA performance characteristics of the kit being validated using thyroid cancer cell lines (T238, SW1736, N-Thy, Cal62, BCPAP, OGK-M, and Hth7) with known status of the BRAF V600E [Figure 1]. All the DNA samples were amplified for beta-globin as a quality control to verify the suitability of DNA. | Figure 1: Polymerase chain reaction results showing B-type Raf kinase V600E amplification in thyroid cancer cell lines
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Treatment philosophy
All the patients of well-differentiated thyroid cancers had a standard evaluation with fine-needle aspiration cytology and an ultrasound of the neck. Imaging with a computed tomography/magnetic resonance imaging scan of the neck was done in the locally advanced thyroid cancers as deemed appropriate. Seven patients were deemed low risk and underwent a hemithyroidectomy. The remaining 72 patients underwent a total thyroidectomy with a central compartment neck dissection. Thirteen patients were initially operated outside and underwent a completion surgery at our center. Four patients of locally advanced thyroid cancers underwent a tracheal resection. Lateral neck dissections were done only in the event of a cytologically confirmed neck nodal metastasis. The high risk and select intermediate risk patients underwent radioiodine ablation and were subsequently followed up on suppressive doses of thyroxine. The follow-up protocol was at 3 monthly intervals for the first 2 years, 6 monthly intervals for the next 3 years, and yearly subsequently. The follow-up included history, clinical examination, serum thyroglobulin, and ultrasound neck. Iodine-131 scans were done for 2 years and were repeated as deemed appropriate. Patterns of failure and survival outcomes were documented for all patients.
| » Results | | |
Seventy-nine patients with well-differentiated thyroid cancers managed in the years 2005 and 2006 were included in the study. The median follow-up of our cohort was 96 months. The median age was 40 years (Range: 15–83 years). There was a significant female preponderance (65.8% [52/79]). Among the histological variants, 67% (53/79) were diagnosed as conventional papillary thyroid cancers, 21.5% (17/79) were diagnosed as follicular variants of PTC, and 10% (8/79) were diagnosed as follicular carcinoma. ETS was found in 18.9% (15/64) of patients and N1b status was noted in 55% (44/79) of patients.
B-type Raf kinase mutation frequency in our cohort
The prevalence of BRAF V600E mutation detected by qPCR in our entire cohort of 79 patients was 31.6% (25/79). We did not find any other type of BRAF mutations, namely, V600K (Val600Lys), V600D (Val600Asp), V600R (Val600Arg), and V600M (Val600Met) that we additionally tested in any of the patient samples.
Frequency of B-type Raf kinase V600E mutation was significantly high in conventional papillary thyroid cancers compared to other histology types
Among the patients with conventional PTC, the prevalence of BRAF V600E mutation was 39.6% (21/53). Compared to follicular variants and follicular cancers, the prevalence of BRAF V600 mutation was significantly higher in conventional papillary thyroid cancers (P = 0.030). Since the association of BRAF mutations was more significant in conventional papillary thyroid cancers, we have shown the correlation of the same as shown in [Table 1] that describes the associations of BRAF V600E mutation status and clinicopathological status of conventional PTC patients. | Table 1: Clinicopathological features of conventional papillary thyroid cancers (n=53) and its association with B-type Raf kinase status
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Conventional papillary thyroid cancers with positive B-type Raf kinase V600E mutations were associated with poorer outcome
We found that patients harboring BRAF V600E mutation had a significantly poorer disease-free survival (DFS) (P = 0.05). Among the patients who failed treatment, 60% (9/15) were significantly correlated to have mutant BRAF V600E compared to 68.4% (26/38) patients showing no evidence of disease and harboring wild-type BRAF V600E (P = 0.05 Chi-square = 3.631).
Older age and presence of extrathyroidal spread were significantly involved with poorer disease-free survival in patients with conventional papillary thyroid cancers
Older age (>45 years) was significantly associated with poorer DFS with 81.8% survival among the patients presenting the age group <45 years compared to 55% among patients with aged >45 years (P = 0.005, log rank = 7.738) [Figure 2]. Among the conventional PTCs, 75.4% (40/53) showed no evidence of ETS and we found a significant correlation among the patients with ETS and poorer DFS (P = 0.006; log rank = 7.423) [Figure 3]. | Figure 3: Kaplan–Meier plots showing disease-free survival versus extrathyroidal spread
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Univariate and multivariate analysis of prognostic factors in papillary thyroid cancers
One-way MANOVA revealed a significant multivariate effect for outcome (Wilks λ =0.813, F(4, 48) = 2.765, P = 0.038) [Table 2]. We undertook age, gender, neck node status, metastasis patterns, ETS, and BRAF V600E mutation status to study the prognostication. We found BRAF V600E mutation status (P = 0.058), age (P = 0.036), and ETS (P = 0.018) most importantly involved in predicting a poorer outcome. This model was significant in the multivariate analysis as well (P = 0.038). Cox proportional hazard model showed that older age (>45 years) and ETS was associated with 4 times more hazard of a poorer DFS (P = 0.017; hazard ratio [HR] = 4.157; 95% confidence interval [CI] – 1.329–13.004 (and P = 0.015; HR = 4.198 95% CI – 1.319–13.366) respectively. | Table 2: Univariate and multivariate model to predict prognosis in conventional papillary thyroid cancers
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Risk stratification of patients with conventional PTC based on B-type Raf kinase V600E mutation testing with age and presence of extrathyroidal spread
Interestingly, we found that the presence or absence of BRAF V600E mutations could possibly help in risk stratification of patients with conventional papillary thyroid cancers. Among the PTC patients, the presence of BRAF V600E mutation and an older age of presentation, i.e., >45 years had the worse DFS of 40% constituting the high risk, compared to patients with younger age at presentation <45 years with the mutant BRAF V600E constituting the moderate risk (72.7% and 70%). Patients with younger age (<45 years) and with absence of BRAF V600E mutations constituted the low-risk group with a DFS of 86.4%. The correlations were statistically significant (P = 0.036 log rank = 8.568) [Figure 4]. | Figure 4: Kaplan–Meier plots showing disease-free survival versus age; risk stratified based on B-type Raf kinase V600E mutation status
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Further, patients with mutant BRAF V600E and with ETS had a dismal DFS with 28.6% presenting as higher risk as compared to patients without ETS and absence of BRAF V600E mutation with 84.6% DFS constituting the low-risk group. Patients with BRAF V600E mutation and with no ETS spread and patients with ETS and no BRAF V600E mutation had a DFS of 71.4% and 66.7%, respectively, constituting the moderate-risk group. The associations were found to be statistically significant (P = 0.033 log rank = 8.734) [Figure 5]. | Figure 5: Kaplan–Meier plots showing disease-free survival versus extrathyroidal spread; risk stratified based on B-type Raf kinase V600E mutation status
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| » Discussion | | |
The dawn of the 21st century marked an increasing interest in exploring the role of BRAF gene mutation in the pathogenesis of many cancers.[8] In fact, mutations in the BRAF gene has been reported in about 7%–15% of all human cancers, with about 40%–70% of melanoma reported to be having one of the highest incidences.[9]
The initial reports on the significance of BRAF V600E mutation in the pathogenesis of PTC were noted in the year 2003;[10],[11],[12],[13] subsequently numerous studies had consistently shown a high prevalence of BRAF V600E mutation in thyroid cancer. BRAF V600E mutation is now considered to be one of the most prevalent molecular events in the pathogenesis of PTC in adults.[14]
The BRAF gene, which is localized on chromosome seven codes for the cytoplasmic serine/threonine kinase which influences the activation of MAPKs and this subsequently results in constitutive hyperactivation, proliferation, survival, and oncogenic transformation. Point mutation T1799A is the most common and the most examined mutation of all BRAF gene mutations, and this occurs due to the exchanging of valine to glutamate at residue 600 near the catalytic center of the protein.
Several studies done before have described a high BRAF V600E mutation prevalence's in conventional PTC, ranging between 29% and 83%.[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26] PTC includes a spectrum histological subtypes differing markedly in biological behavior. The aggressive subtypes of PTC include tall cell, columnar cell, diffuse sclerosing, and the hobnail variants. The conventional and follicular variants account for nearly 86%–90% of all PTC. The prevalence of BRAF mutations in our series of conventional PTC was 39.6%. Follicular variant of PTCs harbors BRAF V600E mutation infrequently as was also noted in our series. None of our patients of follicular thyroid cancers harbored BRAF V600 mutations.
A number of single-center studies have reported the association of BRAF V600E mutations with various clinicopathological risk factors such as advanced age, ETS, high nodal positivity, and distant metastasis, but with conflicting results.[7],[13],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28] Nikiforova et al.[7] initially reported an association between BRAF V600E mutations to increasing age, advanced stage, aggressive histology, and extracapsular extension. The authors also showed the presence of the mutation in anaplastic cancers, suggesting a possibility for the mutation to be related to differentiation of PTC. On a different note, two high-volume single-center studies did not show a significant correlation between mutation status and high-risk clinicopathological features. On the other hand, Gouveia et al.[27] reported a BRAF V600E positivity of 73.2% in their cohort of 429 PTC patients; however, this association was not significantly associated with aggressive clinicopathologic features. In yet another study, Ito et al.[28] in their experience of 766 patients with 37% BRAF V600E positivity reported that mutations' positivity was associated with poor cause-specific survival only in patients with high-risk patients. In our study cohort of conventional papillary thyroid cancers, BRAF V600E mutation was significantly associated with N1b neck node status; we found 54.5% (18/33) of the patients with N1b neck nodes harboring a BRAF mutation V600E (P = 0.011).
A vast majority of the PTCs tend to have an excellent prognosis; therefore, the risk of disease recurrence is most frequently analyzed while considering the prognosis. The incidence of relapse/persistent disease is reported to occur in about 10%–30% of the patients with PTC and further; about 5% of the patients are resistant to conventional treatment. 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.
Elisei et al.[30] reported a decrease in overall and disease-free survival in a group of 102 patients who were BRAF V600E mutation positive, strongly suggesting BRAF mutation to be an independent, unfavorable prognostic factor in PTCs. However, similar results could not be replicated in other single-institution studies.[32],[33],[34] These conflicting reports are possibly related to differences in methodology, i.e., group selection, differences in occurrences of BRAF mutation, BRAF identification methodology, and also lack of validations among others.
A number of meta-analyses were carried out in an attempt objectively asses the prognostic significance of BRAF V600E mutation, considering the conflicting reports from the various single-center publications. The meta-analysis by Lee et al.[35] in 2007 and Li et al.[36] in 2012 did not formally analyze the prognostic significance of BRAF mutations. Eight of the 27 papers analyzed in the meta-analysis by Kim et al.[37] reported a significant association between the presence of BRAF V600E mutation and a higher risk of persistent disease or recurrence (2.14-fold higher risk of recurrent/persistent disease). Another meta-analysis by Tufano et al.[38] which analyzed 2740 patients across 14 studies showed a significantly higher risk of relapse (24.9% vs. 12.6%; P < 0.00001) in patients with confirmed BRAF V600E mutation as compared to mutation-negative patients; however, the risk of relapse varied significantly in the papers analyzed, i.e., 11%–40% for BRAF mutation-positive patients to 2%–36% among the BRAF V600E mutation-negative patients. Yet, another meta-analysis by Chen et al.[39] which included 5873 patients across thirty studies showed that BRAF V600E mutations in PTC was significantly associated with older age, ETS, lymph node metastasis, advanced stage, and recurrence.
However, the recent large retrospective international multicenter studies have suggested the association of the BRAF mutations with aggressive clinicopathological characteristics and mortality of PTC indicating that BRAF V600E could be an independent prognostic factor for PTCs.[40],[41]
The adverse prognostic significance of BRAF V600E mutations as also seen in our cohort, paralleled the results of the meta-analysis older age (>45 years), presence of ETS, and BRAF V600E mutation positivity were found to be significant independent prognostic factors in our cohort of PTCs. Our study further showed that BRAF V600E mutations can be used to risk-stratify patients of PTCs when considered along with the other significant adverse prognostic factors, namely, older age and extrathyroidal extension. A similar observation was observed in the multicenter study by Xing et al.,[41] who also reported a worse disease-free survival in BRAF V600 E mutation-positive patients with extracapsular infiltration and with older age (log-rank, 68.9; P < 0.001).
However, despite the mounting evidence, due to a lack of direct influence of BRAF V600E mutation on the increase in the risk of relapse, the most recent ATA guidelines [42] does not allow for a routine application of BRAF status for the initial risk stratification of patients with well-differentiated thyroid cancer. However, guideline does recommend considering BRAF V600E and/or TERT mutation status for continuous risk assessment of relapse.
The tumor-node-metastasis staging classification is the commonly used system for classification of thyroid carcinomas, and in the case of well-differentiated thyroid cancers, the staging system additionally considers age as a prognostic factor. Some centers have developed individualized risk stratified scales for the assessment of prognosis for patients of PTCs. It is prudent to note that a formal assessment of prognosis based on the various prognostic scales is possible only after noting the results of postoperative histopathology. Consequently, these prognostic scales do not offer the possibility for planning the initial treatment, i.e., extent of surgery and only allows for deciding on adjuvant treatments and follow-up protocols. A need for a preoperative prognostic and predictive marker was felt and hence the potential role of BRAF V600E mutation was explored considering its role in potentially influencing the prognosis. Several authors have explored the option of subjecting patients with suspected malignant thyroid nodules to a preoperative BRAF V600E mutation testing along with other molecular markers in an attempt to guide the initial surgical treatment in PTC.[43],[44],[45],[46],[47],[48],[49],[50]
There seems to be a growing consensus that BRAF V600E mutational status should be analyzed in correlation with other molecular and clinicopathological prognostic factors for a better risk stratification.[51],[52] Recent reports suggest that tumors in which BRAF V600E mutation coexists with other mutations such as TERT, PIK3CA, and/or TP53 are characterized by a more aggressive clinical course.[53],[54],[55] It is believed that more accurate prognostication can be made possible with further genetic analysis and study of novel molecular markers.[55],[56],[57],[58],[59],[60],[61]
| » Conclusion | | |
Our study has attempted to study the biological behavior of conventional PTCs with somatic BRAF V600E mutation, whose prevalence was 39.6%. Our study emphatically states that BRAF V600E mutation status is a significant predictor of adverse outcomes in patients with conventional PTCs further; our study suggests a possible risk-stratified approach using age, BRAF V600E mutation status, and ETS, 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. It is believed that a better prognostication can be made possible with incorporation of novel molecular markers, and this knowledge can be applied for personalizing the diagnostic and therapeutic strategies for patients with conventional PTCs.
Acknowledgments
This work was supported by a grant from Indian Co-operative Oncology Network (autonomous body of Indian Society of Medical and Pediatric Oncology) (Registration No: E – 19333 Mumbai, Charity Commissioner, Greater Mumbai Region, Maharashtra State).
Financial support and sponsorship
This work was supported by a grant from Indian Co-operative Oncology Network (autonomous body of Indian Society of Medical and Pediatric Oncology) (Registration No: E – 19333 Mumbai, Charity Commissioner, Greater Mumbai Region, Maharashtra State).
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2]
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