BRAF Mutation Status Concordance Between Primary Cutaneous Melanomas and Corresponding Metastases: A Review of the Latest Evidence

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Revisión de la evidencia actual" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1801 "Ancho" => 3083 "Tamanyo" => 283174 ] ] "descripcion" => array:1 [ "en" => "Real-time quantitative reverse transcription polymerase chain reaction to detect mutations in BRAFV600. A, DNA study of a tumor without the BRAFV600E mutation. Binding with a single probe (for WT) resulted in a single fluorescence signal interpreted to indicate “not mutated.” B, DNA study of a tumor with the BRAFV600E mutation. Binding with 2 probes resulted in emission of 2 types of fluorescence to indicate “mutated.” WT refers to wild-type; Pol, DNA polymerase enzymes; qPCR, quantitative polymerase chain reaction. Source: Adapted from Curry et al.<a class="elsevierStyleCrossRef" href="#bib0445">30</a>" ] ] ] "textoCompleto" => "IntroductionMutation status concordance between primary and metastatic tumors is a critical area of research in oncology that has become even more important with the introduction of therapies that target specific mutations, such as those on the B-Raf proto-oncongene (BRAF).Concordance has been studied intensively in other malignant tumors but not in melanoma. Most such studies have shown high levels of primary–metastatic concordance: in esophageal cancer, 85% concordance for ERBB2 (formerly HER2) tumors<a class="elsevierStyleCrossRef" href="#bib0300">1</a>; in colon cancer, 98% to 100% concordance for BRAF<a class="elsevierStyleCrossRefs" href="#bib0305">2–5</a>; and also in colon cancer, 92% to 100% concordance for the KRAS proto-oncogene (KRAS).<a class="elsevierStyleCrossRefs" href="#bib0305">2,3,6–14</a> Some authors, however, have reported nonnegligible levels of discordance between primary tumors and their corresponding metastases: in esophageal cancer, discordance of 22.5% for ERBB2/HER2,<a class="elsevierStyleCrossRef" href="#bib0370">15</a> and in colon cancer, 32.4% discordance for KRAS.<a class="elsevierStyleCrossRefs" href="#bib0320">5,16</a>Few studies have analyzed mutation concordance in melanoma, however, and the results are heterogeneous. Some authors have reported high concordance<a class="elsevierStyleCrossRefs" href="#bib0380">17,18</a> while others have reported levels around 50%.<a class="elsevierStyleCrossRefs" href="#bib0390">19–21</a> Most studies based their findings on only a single method for identifying the mutation and used small sample sizes, undermining the validity of conclusions. This review summarizes the current state of knowledge concerning BRAF mutation status concordance in cutaneous melanoma, with reference to the various methods used to identify mutations in clinical practice.BRAF Mutation in MelanomaThe BRAF protein, a key participant in the mitogen-activated protein-kinase (MAPK) pathway, is coded by the BRAF oncogene on chromosome 7 (7q34).<a class="elsevierStyleCrossRef" href="#bib0405">22</a> One of the most common mutations—V600E at the nucleotide position of codon 600 on exon 15—leads to a change of valine to glutamic acid (GTG>GAG) in the protein. V600E occurs in 85% to 90% of cases.<a class="elsevierStyleCrossRefs" href="#bib0405">22–24</a> The next most common mutation, V600K (GTG>AAG), causes a valine to lysine change and has been reported to occur in 20% to 21% of cases.<a class="elsevierStyleCrossRefs" href="#bib0420">25–28</a> However, the prevalence in some populations is higher.<a class="elsevierStyleCrossRefs" href="#bib0420">25,28</a> Other less frequent mutations are V600R (GTG>AGG), V600D (GTG>GAT), V600E2 (GTG>GAA), V600A, V600G, K601N, K601E, L597R, L597Q, G596R, and D594N.<a class="elsevierStyleCrossRefs" href="#bib0440">29,30</a>Alterations in the BRAF protein lead to constitutive activation of the MAPK pathway, obviating the need for Ras activation. Mutation increases the protein's kinase activity 10-fold over the activity coded by unmutated, wild-type BRAF (BRAFWT)<a class="elsevierStyleCrossRefs" href="#bib0405">22,31</a> and leads to neoplastic cell proliferation by continuous transcription. Somatic alterations in the BRAF oncogene are more common in cutaneous melanomas than in other tumors.<a class="elsevierStyleCrossRef" href="#bib0405">22</a> This mutation, found in 50% to 70% of melanomas, is far more frequent than others, such as neuroblastoma Ras oncogene (NRAS) or p16 and p53 tumor suppressor gene mutations.<a class="elsevierStyleCrossRefs" href="#bib0455">32,33</a>Detecting BRAF MutationsSeveral methods are available for detecting BRAF mutations. The choice of one over another is based on ease or provision of rapid results, on sensitivity or specificity, and on cost.SequencingSanger sequencing and pyrosequencing are the most widely used methods for determining mutation status in research. For many years Sanger sequencing of DNA previously amplified by polymerase chain reaction (PCR) was considered the reference method for detecting acquired mutations in tumors and for sequencing the human genome. This technique can detect base substitutions, deletions, and insertions but is unable to detect alterations in duplicated chromosomes or translocations.<a class="elsevierStyleCrossRef" href="#bib0445">30</a> This type of sequencing requires time (18 to 19hours), special equipment that is not available in many laboratories, and qualified staff to interpret the results. The Sanger method is highly specific, but its main limitation is that sensitivity is low (92.5%),<a class="elsevierStyleCrossRef" href="#bib0465">34</a> obliging a tumor load of up to 5% in samples.<a class="elsevierStyleCrossRef" href="#bib0445">30</a> The high rate of false negatives increases the risk that patients who do in fact carry the mutation might not be treated with BRAF protein inhibitors (BRAFi).Pyrosequencing, or sequencing by synthesis, relies on detecting the release of pyrophosphate by DNA polymerase on incorporation of the next complementary nucleotide in the DNAss chain. To sequence in this way, DNA is amplified by PCR, followed by hybridization of the DNAss chain with a primer before incubation with enzymes. The strand is washed in sequentially added solutions of A, C, G, and T nucleotides. The pyrophosphate released on incorporation of a nucleotide reacts with the adenosine triphosphate sulfurylase and luciferase enzymes to produce light (chemiluminescence). The light produced is detected and graphed as a peak in a pyrogram (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Intensity, indicated by the height of the peak, reveals whether more than a single nucleotide is present.<a class="elsevierStyleCrossRefs" href="#bib0470">35,36</a> This approach detects not only a mutation's presence or absence but also the proportion of DNA carrying the mutation. Pyrosequencing has proven to be much more sensitive than Sanger sequencing,<a class="elsevierStyleCrossRef" href="#bib0445">30</a> and it detects not only the BRAFV600E mutation but also less frequent ones (V600K, V600D, V600R, and K601E).<a class="elsevierStyleCrossRefs" href="#bib0445">30,34</a> The technique is rapid (completed in <24hours), but errors are frequent when a nucleotide is sequenced 6 or 7 times (homopolymers). Moreover, whereas Sanger sequencing detects strands up to 800 to 1000 nucleotides long, pyrosequencing is only able to detect strands that are 300 to 500 nucleotides long. The main disadvantage of pyrosequencing is the high cost of reagents and the need for special equipment that is not always available in conventional laboratories.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Real-Time PCRDiagnostic tests based on real-time quantitative reverse transcription PCR (RT-qPCR) are now the most widely used in clinical laboratories to detect mutations in tumor samples. This approach is rapid (<8hours) and offers a level of sensitivity (97.5%<a class="elsevierStyleCrossRefs" href="#bib0465">34,37,38</a>) that is superior to that of the Sanger method. RT-qPCR uses a thermal cycler and fluorescence sensors (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>) to detect DNA mutations in formalin-fixed, paraffin-embedded tissue. To study the presence or absence of mutations in the BRAF oncogene, a specific sequence on exon 15 is targeted. RT-qPCR is therefore both rapid and economical. Three samples can be analyzed simultaneously without loss of reagent yield, and the technique uses devices already present in the laboratory for detecting other mutations of interest in routine clinical practice (eg, KRAS in colon cancer or the EGFR in nonsmall cell lung cancer).<elsevierMultimedia ident="fig0010"></elsevierMultimedia>Several devices have recently been approved for RT-qPCR. The Cobas 4800 BRAFV600 Mutation Test (Roche Molecular Systems) has become the most widely used platform since its approval by the US Food and Drug Administration (FDA) for patients who are candidates for treatment with vemurafenib. The clinical usefulness of the Cobas test was validated for identifying tumors carrying the BRAFV600E mutation, which it detected in 100% of samples.<a class="elsevierStyleCrossRef" href="#bib0490">39</a> It also proved useful for other mutations: BRAFV600K (detected in 70% of samples),<a class="elsevierStyleCrossRef" href="#bib0490">39</a>BRAFV600D and BRAFV600E2.<a class="elsevierStyleCrossRefs" href="#bib0485">38,40</a> The lower limit of detection of the Cobas platform is 4.4% of mutated alleles per 1.25ng/μL. However, other mutations, such as V600K and V600E2, require higher percentages (31% and 68%, respectively).<a class="elsevierStyleCrossRef" href="#bib0445">30</a> Errors are often related to the presence of melanin, an inhibitor of PCR.When RT-qPCR was used by Yancovitzetal.<a class="elsevierStyleCrossRef" href="#bib0400">21</a> to detect the BRAFV600E mutation in 112 melanoma samples, they found that 75.9% were positive (66.7% of primary tumors and 77.7% of metastases), whereas conventional sequencing found only 32.1% of the cases in the same samples (38.9% in primary tumors and 30.9% in metastases). Moreover, all of the tumor mutations identified by conventional sequencing were found by RT-qPCR.This technique was also shown to be useful for cytologic analysis of fine-needle aspirate biopsies.<a class="elsevierStyleCrossRef" href="#bib0500">41</a> Agreement between RT-qPCR and Sanger sequencing was 93% in 117 paraffin-embedded biopsies that were obtained for cytology and were composed of at least 50% tumor cells.Anti-VE1 Monoclonal AntibodyA monoclonal antibody for VE1, the protein expressed by the BRAFV600E mutation, can be detected immunohistochemically in paraffin-embedded material from tumor samples.<a class="elsevierStyleCrossRefs" href="#bib0505">42–44</a> Sensitivity for the V600E mutation has been reported to be 100%,<a class="elsevierStyleCrossRefs" href="#bib0465">34,45</a> but other mutations (including BRAFV600K) have not been detected. Given that immunohistochemistry is a rapid, economical procedure within the scope of routine practice in hospital pathology laboratories, it promises to be viable for clinical use. However, neither the US FDA or the European Medicines Agency have yet approved it for use in candidates for BRAFi therapy. Moreover, since this therapy has been shown to be effective in treating tumors with the V600K mutation, the exclusive use of immunohistochemistry would not identify BRAFi treatment candidates who have the V600K mutation.Liquid BiopsySo-called liquid biopsy has been studied in the context of other solid tumors<a class="elsevierStyleCrossRef" href="#bib0525">46</a> and is gaining importance in the evaluation of melanoma. The term encompasses the detection of circulating tumor DNA (ctDNA) and circulating microRNA.<a class="elsevierStyleCrossRef" href="#bib0530">47</a> The use of RT-qPCR in plasma to detect either ctDNA or circulating tumor cells released after apoptosis or necrosis is a promising approach for following patients with metastatic melanoma. The method is currently being validated not only for detecting primary–metastatic mutation discordance but also for evaluating response to treatment and recurrence.It therefore seems reasonable to combine immunohistochemistry with molecular approaches such as RT-qPCR or pyrosequencing to identify BRAF mutations in patients with metastatic melanoma.Primary–Metastatic BRAF Mutation Status ConcordanceGiven that primary–metastatic mutation status discordance has been seen in other tumors<a class="elsevierStyleCrossRef" href="#bib0535">48</a> and is a reason for resistance to treatment, this possibility must be studied in cancer patients who are candidates for targeted therapy. Other melanoma mutations (on NRAS, for example) have been shown to have high concordance with the primary tumor.<a class="elsevierStyleCrossRef" href="#bib0540">49</a>Our review of studies of BRAF mutation status concordance in melanoma to date reveals that most have evaluated small samples.<a class="elsevierStyleCrossRefs" href="#bib0390">19–21</a> Exceptions are a study by Colombinoetal.<a class="elsevierStyleCrossRef" href="#bib0380">17</a> and a recent one by our group.<a class="elsevierStyleCrossRef" href="#bib0545">50</a> Reviewing the concordance rates in the published studies, we can observe that they show different results (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Colombinoetal.<a class="elsevierStyleCrossRef" href="#bib0380">17</a> reported a low rate of the discordant cases (in 15 of 165 cases), 53% of the primary tumors were BRAFWT with mutant BRAF (BRAFM) in metastasis, whereas 47% primary tumors tested BRAFM but had BRAFWT metastases.Our group observed a higher rate of concordance in a larger multicenter study of 140 primary tumors and 171 metastatic pairs.<a class="elsevierStyleCrossRef" href="#bib0545">50</a> Using the RT-qPCR Cobas® platform we found concordance in 83.6% of the pairs. When we added immunohistochemistry findings for VE1 protein expression and Sanger sequencing, concordance reached 100%.Other authors studying smaller samples have also reported high rates of concordance. In a study of 71 primary melanomas, Omholtetal.<a class="elsevierStyleCrossRef" href="#bib0385">18</a> were able to evaluate 51 matched metastatic tumors, although they did not specify the type of metastasis. There were only 2 discordant cases, both primary BRAFWT tumors with BRAFM metastases. This study found in 17 consecutive cases of metastasis only a single discordant pair in a patient with a primary BRAFM tumor with both BRAFM and BRAFWT metastases. Saroufimetal.<a class="elsevierStyleCrossRef" href="#bib0550">51</a> studied 40 primary tumors with paired metastases, of which only 33 had adequate material to complete the evaluation. In 6 of the cases, RT-qPCR findings could not be evaluated, so the authors resorted to immunohistochemistry. They confirmed primary–metastatic concordance in 26 of the 33 cases (79%). Five discordant cases were BRAFM primary tumors paired with BRAFWT metastases, and 2 were BRAFWT primary tumors paired with BRAFM metastases. Akslenetal.<a class="elsevierStyleCrossRef" href="#bib0555">52</a> studied 18 cases and were able to report results for 17 pairs. Only 2 pairs, both BRAFWT primary tumors, were discordant. Busametal.<a class="elsevierStyleCrossRef" href="#bib0560">53</a> studied cases in which mutation status results obtained by sequencing were available for comparison with the results of immunohistochemical staining for VE1 protein expression. Among them was a BRAFM primary tumor with concordant metastasis.However, when even smaller samples were studied, the authors saw higher proportions of discordance. Houbenetal.<a class="elsevierStyleCrossRef" href="#bib0565">54</a> studied NRAS and BRAF status in 24 pairs, finding 7 cases of primary–metastatic discordance. Three were in BRAFWT primary tumors with BRAFM (V600E, V600R, and V600K) metastases. Another 2 cases were in mutant BRAFV600E primary tumors with BRAFWT metastases that acquired NRAS mutations, which had not been present in the primary tumor. The remaining two cases had only NRAS mutation discordance. Yancovitzetal.<a class="elsevierStyleCrossRef" href="#bib0400">21</a> studied concordance in 18 primary tumors with BRAF and their corresponding metastases. The 8 discordant cases were in 6 BRAFWT primary tumors with BRAFM metastases, plus 2 BRAFM primary tumors with BRAFWT metastases. The mutation status of 9 of the primary tumors was heterogeneous, with more than a single cell population within the same tumor, a phenomenon that has been described by other authors.<a class="elsevierStyleCrossRefs" href="#bib0570">55,56</a> Shinozakietal.<a class="elsevierStyleCrossRef" href="#bib0390">19</a> detected primary–metastatic discordance in 8 out of 13 cases. All were BRAFWT primary tumors with BRAFM metastases. The authors suggested the mutations might have been acquired during disease progression. Finally, the selection of BRAFM alleles during the progression of initially heterogeneous primary tumors was observed by Linetal.<a class="elsevierStyleCrossRef" href="#bib0395">20</a> in samples from 3 patients. In 1 of the cases, the mutation was found on recurrence of a primary tumor that had not initially been positive for the mutation. In another case, the primary tumor was heterogeneous (BRAFWT plus BRAFV600K) and 7 of the 9 visceral and subcutaneous metastases showed a predominance of BRAFV600K. The third patient had a primary tumor in which BRAFV600K was present, but node metastases contained more of mutated alleles. The authors of this study pointed out that even acral and mucosal melanomas can harbor small BRAFM subpopulations in the primary tumor that can later predominate on metastasis.Concordance in Subsequent MetastasisSeveral concordance studies have analyzed DNA sequencing data for several metastases in the same patient even though mutation status for the primary tumor was unavailable. In an interesting study in 15 patients, Sigalottietal.<a class="elsevierStyleCrossRef" href="#bib0580">57</a> analyzed 15 initial metastases and 19 subsequent metastases. They found that BRAF mutation status (3 BRAFWT and 12 BRAFM) was maintained in all but 2 cases, in which later metastases from the primary tumors were homozygous although the earlier metastatic tumors had been heterozygous. These observations suggest the stability of established mutation status in metastatic melanoma regardless of location or time frame. Saroufimetal.<a class="elsevierStyleCrossRef" href="#bib0585">58</a> also studied subsequent metastases and Niessneretal.<a class="elsevierStyleCrossRef" href="#bib0590">59</a> studied paired cerebral and extracerebral metastases, finding identical patterns of BRAF, NRAS, and KIT oncogene mutations. In contrast, when Changetal.<a class="elsevierStyleCrossRef" href="#bib0575">56</a> sequenced DNA in frozen tissue in 3 cases of multiple metastases, they found complete mutation status concordance in only a single case. The other 2 were discordant.DiscussionDiscordance between primary tumors and their corresponding metastasis can be explained by a theory recently advanced by Yancovitzetal.,<a class="elsevierStyleCrossRef" href="#bib0400">21</a> according to which different subclone populations can coexist in a single tumor (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>), a status referred to as intratumoral heterogeneity. The presence of different cell populations, some carrying a mutation and others not, allows both BRAFM and BRAFWT metastases to develop. Similarly, resistance to targeted therapy as well as disease progression through clonal selection, which has been observed in some patients who initially responded well to BRAFi therapy, can be explained by both intratumoral and intertumoral heterogeneity (presence of different subclones in primary and metastatic tumors).<elsevierMultimedia ident="fig0015"></elsevierMultimedia>The studies in the larger sample sizes suggest that discordance is low or nearly absent in cutaneous melanoma. The findings of discordance in some studies could be attributed to the presence of mutations other than V600E or to the use of a single detection method, as some have low sensitivity. The study with the largest sample size, one which also used the largest number of detection techniques, found 100% concordance,<a class="elsevierStyleCrossRef" href="#bib0545">50</a> supporting the theory that melanoma mutation status stays stable during progression.In any case, though the prevalence of discordant metastases may be low, the possibility should not be ignored given that patients with discordant tumors who might be candidates for BRAFi therapy may be affected. Not detecting mutation status might deny them the treatment.It therefore seems reasonable to propose that the ideal tissue for mutation status assessment would come from the most recent metastasis. However, when such tissue is unavailable for analysis, the high levels of concordance found in larger studies suggests that mutations in the primary tumor should be studied instead. Similarly, new metastases that occur when progression takes place during BRAFi therapy should be analyzed for clones that do not carry the same mutation. Moreover, combining techniques—such as RT-qPCR and immunohistochemistry—would increase detection sensitivity.Ethical DisclosuresProtection of human and animal subjectsThe authors declare that no experiments were performed on humans or animals for this investigation.Data confidentialityThe authors declare that no private patient data are disclosed in this article.Right to privacy and informed consentThe authors declare that no private patient data are disclosed in this article.Conflicts of InterestThe authors declare that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres949053" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec921161" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres949054" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec921162" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "BRAF Mutation in Melanoma" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Detecting BRAF Mutations" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Sequencing" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Real-Time PCR" ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "Anti-VE1 Monoclonal Antibody" ] 3 => array:2 [ "identificador" => "sec0035" "titulo" => "Liquid Biopsy" ] ] ] 7 => array:3 [ "identificador" => "sec0040" "titulo" => "Primary–Metastatic BRAF Mutation Status Concordance" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Concordance in Subsequent Metastasis" ] ] ] 8 => array:2 [ "identificador" => "sec0050" "titulo" => "Discussion" ] 9 => array:3 [ "identificador" => "sec0055" "titulo" => "Ethical Disclosures" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0060" "titulo" => "Protection of human and animal subjects" ] 1 => array:2 [ "identificador" => "sec0065" "titulo" => "Data confidentiality" ] 2 => array:2 [ "identificador" => "sec0070" "titulo" => "Right to privacy and informed consent" ] ] ] 10 => array:2 [ "identificador" => "sec0075" "titulo" => "Conflicts of Interest" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-09-29" "fechaAceptado" => "2016-12-31" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec921161" "palabras" => array:5 [ 0 => "Melanoma" 1 => "Concordance" 2 => "Metastasis" 3 => "BRAF" 4 => "Intratumoral heterogeneity" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec921162" "palabras" => array:5 [ 0 => "Melanoma" 1 => "Concordancia" 2 => "Metástasis" 3 => "BRAF" 4 => "Heterogeneidad intratumoral" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "The identification of B-Raf proto-oncongene (BRAF) mutation and the emergence of targeted therapy marked a turning point in the treatment of melanoma. The study of mutation status concordance between primary tumors and metastases in this cancer has major treatment implications as it facilitates the selection of candidates for targeted therapy. This review analyzes the evidence on the level of mutation status concordance between primary tumors and different types of metastases in cutaneous melanoma and provides an overview of the advantages and disadvantages of the various methods used to detect BRAF mutations." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La mutación en el oncogén BRAF en melanoma y la aparición de terapias dirigidas frente a ella han supuesto un antes y un después en el tratamiento de esta enfermedad. El estudio del estado mutacional en las metástasis y su concordancia con el tumor primario tiene además una gran implicación terapéutica en estos pacientes, pues permite seleccionar candidatos a estos tratamientos. El objetivo de esta revisión es conocer las evidencias disponibles sobre el grado de concordancia en los distintos tipos de metástasis en el melanoma cutáneo, así como las ventajas y desventajas de los distintos métodos de detección de la mutación en BRAF." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Godoy-Gijón E, Yuste-Chaves M, Santos-Briz Á. Concordancia mutacional de BRAF entre melanoma primario cutáneo y sus correspondientes metástasis. Revisión de la evidencia actual. Actas Dermosifiliogr. 2017;108:894–901." ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1344 "Ancho" => 1584 "Tamanyo" => 106369 ] ] "descripcion" => array:1 [ "en" => "Example of a pyrogram." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1801 "Ancho" => 3083 "Tamanyo" => 283174 ] ] "descripcion" => array:1 [ "en" => "Real-time quantitative reverse transcription polymerase chain reaction to detect mutations in BRAFV600. A, DNA study of a tumor without the BRAFV600E mutation. Binding with a single probe (for WT) resulted in a single fluorescence signal interpreted to indicate “not mutated.” B, DNA study of a tumor with the BRAFV600E mutation. Binding with 2 probes resulted in emission of 2 types of fluorescence to indicate “mutated.” WT refers to wild-type; Pol, DNA polymerase enzymes; qPCR, quantitative polymerase chain reaction. Source: Adapted from Curry et al.<a class="elsevierStyleCrossRef" href="#bib0445">30</a>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1632 "Ancho" => 1914 "Tamanyo" => 323377 ] ] "descripcion" => array:1 [ "en" => "Intratumoral heterogeneity. Presence in a single tumor of subclones carrying the BRAFV600E mutation in a mainly BRAFWT primary tumor." ] ] 3 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "Abbreviations: Conc, concordance; Disc, discordance; IH, immunohistochemistry; PCR, polymerase chain reaction; SS, Sanger sequencing; BRAF, B-Raf proto-oncogene; M (superscript), mutant; WT (superscript), wild-type." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">N, Primary Tumor \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">N, Metastatis \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="3" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Lymphatic</th><th class="td" title="table-head " colspan="3" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Soft-Tissue</th><th class="td" title="table-head " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Visceral</th><th class="td" title="table-head " align="left" valign="top" scope="col">Method \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Discordance \t\t\t\t\t\t\n \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">N \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Conc \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Disc \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">N \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Conc \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Disc \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">N \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Conc \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Disc \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Riveiro et al.<a class="elsevierStyleCrossRef" href="#bib0545">50</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">140 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">171 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">100 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">100 (100%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">62 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">62 (100%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9 (100%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PCR+IH+SS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Colombino et al.<a class="elsevierStyleCrossRef" href="#bib0380">17</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">102 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">165 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">84 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">78 (93%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6 (7%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">36 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">29 (81%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7 (19%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">45 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">43 (96%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (4%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">BRAFM/BRAFWT \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Saroufim et al.<a class="elsevierStyleCrossRef" href="#bib0550">51</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">33 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">33 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">22 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">20 (91%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (9%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 (57%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 (43%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (50%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (50%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PCR+IH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">BRAFM/BRAFWT \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Shinozaki et al.<a class="elsevierStyleCrossRef" href="#bib0390">19</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7 (58%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 (42%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 (100%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">BRAFWT \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Lin et al.<a class="elsevierStyleCrossRef" href="#bib0395">20</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (40%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 (60%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (100%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 (33%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (67%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">BRAFM/BRAFWT \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="14" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Omholt et al.<a class="elsevierStyleCrossRef" href="#bib0385">18</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">71 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">51b \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">49 (96%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (4%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">BRAFWT \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Houben et al.<a class="elsevierStyleCrossRef" href="#bib0565">54</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">24b \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">19 (79%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 (21%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">BRAFM/BRAFWT \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Akslen et al.<a class="elsevierStyleCrossRef" href="#bib0555">52</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">17 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">17b \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">15 (88%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (12%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">BRAFWT \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Yancovitz et al.<a class="elsevierStyleCrossRef" href="#bib0400">21</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">18b \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10 (56%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8 (44%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SS+PCR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">BRAFM/BRAFWT \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Busam et al.<a class="elsevierStyleCrossRef" href="#bib0560">53</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1b \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 (100%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SS+IH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1607259.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Type of metastasis was specified by the first 5 author groups; 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Review

BRAF Mutation Status Concordance Between Primary Cutaneous Melanomas and Corresponding Metastases: A Review of the Latest Evidence

Concordancia mutacional de BRAF entre melanoma primario cutáneo y sus correspondientes metástasis. Revisión de la evidencia actual

E. Godoy-Gijóna,

Corresponding author

e.godoy.gijon@gmail.com

Corresponding author.

, M. Yuste-Chavesb, Á. Santos-Brizc

a Servicio de Dermatología, Complejo Asistencial de Zamora, Zamora, España

b Servicio de Dermatología, Complejo Asistencial Universitario de Salamanca, Salamanca, España

c Servicio de Anatomía Patológica, Complejo Asistencial Universitario de Salamanca, Salamanca, España

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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Real-time quantitative reverse transcription polymerase chain reaction to detect mutations in <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">V600</span>&#46; A&#44; DNA study of a tumor without the <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">V600E</span> mutation&#46; Binding with a single probe &#40;for WT&#41; resulted in a single fluorescence signal interpreted to indicate &#8220;not mutated&#46;&#8221; B&#44; DNA study of a tumor with the <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">V600E</span> mutation&#46; Binding with 2 probes resulted in emission of 2 types of fluorescence to indicate &#8220;mutated&#46;&#8221; WT refers to wild-type&#59; Pol&#44; DNA polymerase enzymes&#59; qPCR&#44; quantitative polymerase chain reaction&#46;</p> <p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Source&#58; Adapted from Curry et al&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">30</span></a></p>"
        ]
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Mutation status concordance between primary and metastatic tumors is a critical area of research in oncology that has become even more important with the introduction of therapies that target specific mutations&#44; such as those on the B-Raf proto-oncongene &#40;<span class="elsevierStyleItalic">BRAF</span>&#41;&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Concordance has been studied intensively in other malignant tumors but not in melanoma&#46; Most such studies have shown high levels of primary&#8211;metastatic concordance&#58; in esophageal cancer&#44; 85&#37; concordance for <span class="elsevierStyleItalic">ERBB2</span> &#40;formerly <span class="elsevierStyleItalic">HER2</span>&#41; tumors<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">1</span></a>&#59; in colon cancer&#44; 98&#37; to 100&#37; concordance for <span class="elsevierStyleItalic">BRAF</span><a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">2&#8211;5</span></a>&#59; and also in colon cancer&#44; 92&#37; to 100&#37; concordance for the KRAS proto-oncogene &#40;<span class="elsevierStyleItalic">KRAS</span>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">2&#44;3&#44;6&#8211;14</span></a> Some authors&#44; however&#44; have reported nonnegligible levels of discordance between primary tumors and their corresponding metastases&#58; in esophageal cancer&#44; discordance of 22&#46;5&#37; for <span class="elsevierStyleItalic">ERBB2</span>&#47;<span class="elsevierStyleItalic">HER2</span>&#44;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">15</span></a> and in colon cancer&#44; 32&#46;4&#37; discordance for <span class="elsevierStyleItalic">KRAS</span>&#46;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">5&#44;16</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Few studies have analyzed mutation concordance in melanoma&#44; however&#44; and the results are heterogeneous&#46; Some authors have reported high concordance<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">17&#44;18</span></a> while others have reported levels around 50&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">19&#8211;21</span></a> Most studies based their findings on only a single method for identifying the mutation and used small sample sizes&#44; undermining the validity of conclusions&#46; This review summarizes the current state of knowledge concerning <span class="elsevierStyleItalic">BRAF</span> mutation status concordance in cutaneous melanoma&#44; with reference to the various methods used to identify mutations in clinical practice&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030"><span class="elsevierStyleItalic">BRAF</span> Mutation in Melanoma</span><p id="par0020" class="elsevierStylePara elsevierViewall">The BRAF protein&#44; a key participant in the mitogen-activated protein-kinase &#40;MAPK&#41; pathway&#44; is coded by the <span class="elsevierStyleItalic">BRAF</span> oncogene on chromosome 7 &#40;7q34&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">22</span></a> One of the most common mutations&#8212;V600E at the nucleotide position of codon 600 on exon 15&#8212;leads to a change of valine to glutamic acid &#40;GTG<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>GAG&#41; in the protein&#46; V600E occurs in 85&#37; to 90&#37; of cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">22&#8211;24</span></a> The next most common mutation&#44; V600K &#40;GTG<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>AAG&#41;&#44; causes a valine to lysine change and has been reported to occur in 20&#37; to 21&#37; of cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">25&#8211;28</span></a> However&#44; the prevalence in some populations is higher&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">25&#44;28</span></a> Other less frequent mutations are V600R &#40;GTG<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>AGG&#41;&#44; V600D &#40;GTG<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>GAT&#41;&#44; V600E2 &#40;GTG<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>GAA&#41;&#44; V600A&#44; V600G&#44; K601N&#44; K601E&#44; L597R&#44; L597Q&#44; G596R&#44; and D594N&#46;<a class="elsevierStyleCrossRefs" href="#bib0440"><span class="elsevierStyleSup">29&#44;30</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Alterations in the BRAF protein lead to constitutive activation of the MAPK pathway&#44; obviating the need for Ras activation&#46; Mutation increases the protein&#39;s kinase activity 10-fold over the activity coded by unmutated&#44; wild-type <span class="elsevierStyleItalic">BRAF</span> &#40;<span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">WT</span>&#41;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">22&#44;31</span></a> and leads to neoplastic cell proliferation by continuous transcription&#46; Somatic alterations in the <span class="elsevierStyleItalic">BRAF</span> oncogene are more common in cutaneous melanomas than in other tumors&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">22</span></a> This mutation&#44; found in 50&#37; to 70&#37; of melanomas&#44; is far more frequent than others&#44; such as neuroblastoma Ras oncogene &#40;<span class="elsevierStyleItalic">NRAS</span>&#41; or p16 and p53 tumor suppressor gene mutations&#46;<a class="elsevierStyleCrossRefs" href="#bib0455"><span class="elsevierStyleSup">32&#44;33</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Detecting <span class="elsevierStyleItalic">BRAF</span> Mutations</span><p id="par0030" class="elsevierStylePara elsevierViewall">Several methods are available for detecting <span class="elsevierStyleItalic">BRAF</span> mutations&#46; The choice of one over another is based on ease or provision of rapid results&#44; on sensitivity or specificity&#44; and on cost&#46;</p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Sequencing</span><p id="par0035" class="elsevierStylePara elsevierViewall">Sanger sequencing and pyrosequencing are the most widely used methods for determining mutation status in research&#46; For many years Sanger sequencing of DNA previously amplified by polymerase chain reaction &#40;PCR&#41; was considered the reference method for detecting acquired mutations in tumors and for sequencing the human genome&#46; This technique can detect base substitutions&#44; deletions&#44; and insertions but is unable to detect alterations in duplicated chromosomes or translocations&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">30</span></a> This type of sequencing requires time &#40;18 to 19<span class="elsevierStyleHsp" style=""></span>hours&#41;&#44; special equipment that is not available in many laboratories&#44; and qualified staff to interpret the results&#46; The Sanger method is highly specific&#44; but its main limitation is that sensitivity is low &#40;92&#46;5&#37;&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">34</span></a> obliging a tumor load of up to 5&#37; in samples&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">30</span></a> The high rate of false negatives increases the risk that patients who do in fact carry the mutation might not be treated with BRAF protein inhibitors &#40;BRAFi&#41;&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Pyrosequencing&#44; or sequencing by synthesis&#44; relies on detecting the release of pyrophosphate by DNA polymerase on incorporation of the next complementary nucleotide in the DNAss chain&#46; To sequence in this way&#44; DNA is amplified by PCR&#44; followed by hybridization of the DNAss chain with a primer before incubation with enzymes&#46; The strand is washed in sequentially added solutions of A&#44; C&#44; G&#44; and T nucleotides&#46; The pyrophosphate released on incorporation of a nucleotide reacts with the adenosine triphosphate sulfurylase and luciferase enzymes to produce light &#40;chemiluminescence&#41;&#46; The light produced is detected and graphed as a peak in a pyrogram &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Intensity&#44; indicated by the height of the peak&#44; reveals whether more than a single nucleotide is present&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">35&#44;36</span></a> This approach detects not only a mutation&#39;s presence or absence but also the proportion of DNA carrying the mutation&#46; Pyrosequencing has proven to be much more sensitive than Sanger sequencing&#44;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">30</span></a> and it detects not only the <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">V600E</span> mutation but also less frequent ones &#40;V600K&#44; V600D&#44; V600R&#44; and K601E&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0445"><span class="elsevierStyleSup">30&#44;34</span></a> The technique is rapid &#40;completed in &#60;<span class="elsevierStyleHsp" style=""></span>24<span class="elsevierStyleHsp" style=""></span>hours&#41;&#44; but errors are frequent when a nucleotide is sequenced 6 or 7 times &#40;homopolymers&#41;&#46; Moreover&#44; whereas Sanger sequencing detects strands up to 800 to 1000 nucleotides long&#44; pyrosequencing is only able to detect strands that are 300 to 500 nucleotides long&#46; The main disadvantage of pyrosequencing is the high cost of reagents and the need for special equipment that is not always available in conventional laboratories&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Real-Time PCR</span><p id="par0045" class="elsevierStylePara elsevierViewall">Diagnostic tests based on real-time quantitative reverse transcription PCR &#40;RT-qPCR&#41; are now the most widely used in clinical laboratories to detect mutations in tumor samples&#46; This approach is rapid &#40;&#60;<span class="elsevierStyleHsp" style=""></span>8<span class="elsevierStyleHsp" style=""></span>hours&#41; and offers a level of sensitivity &#40;97&#46;5&#37;<a class="elsevierStyleCrossRefs" href="#bib0465"><span class="elsevierStyleSup">34&#44;37&#44;38</span></a>&#41; that is superior to that of the Sanger method&#46; RT-qPCR uses a thermal cycler and fluorescence sensors &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41; to detect DNA mutations in formalin-fixed&#44; paraffin-embedded tissue&#46; To study the presence or absence of mutations in the <span class="elsevierStyleItalic">BRAF</span> oncogene&#44; a specific sequence on exon 15 is targeted&#46; RT-qPCR is therefore both rapid and economical&#46; Three samples can be analyzed simultaneously without loss of reagent yield&#44; and the technique uses devices already present in the laboratory for detecting other mutations of interest in routine clinical practice &#40;eg&#44; <span class="elsevierStyleItalic">KRAS</span> in colon cancer or the EGFR in nonsmall cell lung cancer&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">Several devices have recently been approved for RT-qPCR&#46; The Cobas 4800 <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">V600</span> Mutation Test &#40;Roche Molecular Systems&#41; has become the most widely used platform since its approval by the US Food and Drug Administration &#40;FDA&#41; for patients who are candidates for treatment with vemurafenib&#46; The clinical usefulness of the Cobas test was validated for identifying tumors carrying the <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">V600E</span> mutation&#44; which it detected in 100&#37; of samples&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">39</span></a> It also proved useful for other mutations&#58; <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">V600K</span> &#40;detected in 70&#37; of samples&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">39</span></a><span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">V600D</span> and <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">V600E2</span>&#46;<a class="elsevierStyleCrossRefs" href="#bib0485"><span class="elsevierStyleSup">38&#44;40</span></a> The lower limit of detection of the Cobas platform is 4&#46;4&#37; of mutated alleles per 1&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;&#956;L&#46; However&#44; other mutations&#44; such as V600K and V600E2&#44; require higher percentages &#40;31&#37; and 68&#37;&#44; respectively&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">30</span></a> Errors are often related to the presence of melanin&#44; an inhibitor of PCR&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">When RT-qPCR was used by Yancovitz<span class="elsevierStyleHsp" style=""></span>et<span class="elsevierStyleHsp" style=""></span>al&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">21</span></a> to detect the <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">V600E</span> mutation in 112 melanoma samples&#44; they found that 75&#46;9&#37; were positive &#40;66&#46;7&#37; of primary tumors and 77&#46;7&#37; of metastases&#41;&#44; whereas conventional sequencing found only 32&#46;1&#37; of the cases in the same samples &#40;38&#46;9&#37; in primary tumors and 30&#46;9&#37; in metastases&#41;&#46; Moreover&#44; all of the tumor mutations identified by conventional sequencing were found by RT-qPCR&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">This technique was also shown to be useful for cytologic analysis of fine-needle aspirate biopsies&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">41</span></a> Agreement between RT-qPCR and Sanger sequencing was 93&#37; in 117 paraffin-embedded biopsies that were obtained for cytology and were composed of at least 50&#37; tumor cells&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Anti-VE1 Monoclonal Antibody</span><p id="par0065" class="elsevierStylePara elsevierViewall">A monoclonal antibody for VE1&#44; the protein expressed by the <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">V600E</span> mutation&#44; can be detected immunohistochemically in paraffin-embedded material from tumor samples&#46;<a class="elsevierStyleCrossRefs" href="#bib0505"><span class="elsevierStyleSup">42&#8211;44</span></a> Sensitivity for the V600E mutation has been reported to be 100&#37;&#44;<a class="elsevierStyleCrossRefs" href="#bib0465"><span class="elsevierStyleSup">34&#44;45</span></a> but other mutations &#40;including <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">V600K</span>&#41; have not been detected&#46; Given that immunohistochemistry is a rapid&#44; economical procedure within the scope of routine practice in hospital pathology laboratories&#44; it promises to be viable for clinical use&#46; However&#44; neither the US FDA or the European Medicines Agency have yet approved it for use in candidates for BRAFi therapy&#46; Moreover&#44; since this therapy has been shown to be effective in treating tumors with the V600K mutation&#44; the exclusive use of immunohistochemistry would not identify BRAFi treatment candidates who have the V600K mutation&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Liquid Biopsy</span><p id="par0070" class="elsevierStylePara elsevierViewall">So-called liquid biopsy has been studied in the context of other solid tumors<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">46</span></a> and is gaining importance in the evaluation of melanoma&#46; The term encompasses the detection of circulating tumor DNA &#40;ctDNA&#41; and circulating microRNA&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">47</span></a> The use of RT-qPCR in plasma to detect either ctDNA or circulating tumor cells released after apoptosis or necrosis is a promising approach for following patients with metastatic melanoma&#46; The method is currently being validated not only for detecting primary&#8211;metastatic mutation discordance but also for evaluating response to treatment and recurrence&#46;<span class="elsevierStyleVsp" style="height:0.5px"></span></p><p id="par0075" class="elsevierStylePara elsevierViewall">It therefore seems reasonable to combine immunohistochemistry with molecular approaches such as RT-qPCR or pyrosequencing to identify <span class="elsevierStyleItalic">BRAF</span> mutations in patients with metastatic melanoma&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Primary&#8211;Metastatic <span class="elsevierStyleItalic">BRAF</span> Mutation Status Concordance</span><p id="par0080" class="elsevierStylePara elsevierViewall">Given that primary&#8211;metastatic mutation status discordance has been seen in other tumors<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">48</span></a> and is a reason for resistance to treatment&#44; this possibility must be studied in cancer patients who are candidates for targeted therapy&#46; Other melanoma mutations &#40;on <span class="elsevierStyleItalic">NRAS</span>&#44; for example&#41; have been shown to have high concordance with the primary tumor&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">49</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Our review of studies of <span class="elsevierStyleItalic">BRAF</span> mutation status concordance in melanoma to date reveals that most have evaluated small samples&#46;<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">19&#8211;21</span></a> Exceptions are a study by Colombino<span class="elsevierStyleHsp" style=""></span>et<span class="elsevierStyleHsp" style=""></span>al&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">17</span></a> and a recent one by our group&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">50</span></a> Reviewing the concordance rates in the published studies&#44; we can observe that they show different results &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">Colombino<span class="elsevierStyleHsp" style=""></span>et<span class="elsevierStyleHsp" style=""></span>al&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">17</span></a> reported a low rate of the discordant cases &#40;in 15 of 165 cases&#41;&#44; 53&#37; of the primary tumors were <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">WT</span> with mutant <span class="elsevierStyleItalic">BRAF</span> &#40;<span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">M</span>&#41; in metastasis&#44; whereas 47&#37; primary tumors tested <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">M</span> but had <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">WT</span> metastases&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Our group observed a higher rate of concordance in a larger multicenter study of 140 primary tumors and 171 metastatic pairs&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">50</span></a> Using the RT-qPCR Cobas&#174; platform we found concordance in 83&#46;6&#37; of the pairs&#46; When we added immunohistochemistry findings for VE1 protein expression and Sanger sequencing&#44; concordance reached 100&#37;&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Other authors studying smaller samples have also reported high rates of concordance&#46; In a study of 71 primary melanomas&#44; Omholt<span class="elsevierStyleHsp" style=""></span>et<span class="elsevierStyleHsp" style=""></span>al&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">18</span></a> were able to evaluate 51 matched metastatic tumors&#44; although they did not specify the type of metastasis&#46; There were only 2 discordant cases&#44; both primary <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">WT</span> tumors with <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">M</span> metastases&#46; This study found in 17 consecutive cases of metastasis only a single discordant pair in a patient with a primary <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">M</span> tumor with both <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">M</span> and <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">WT</span> metastases&#46; Saroufim<span class="elsevierStyleHsp" style=""></span>et<span class="elsevierStyleHsp" style=""></span>al&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">51</span></a> studied 40 primary tumors with paired metastases&#44; of which only 33 had adequate material to complete the evaluation&#46; In 6 of the cases&#44; RT-qPCR findings could not be evaluated&#44; so the authors resorted to immunohistochemistry&#46; They confirmed primary&#8211;metastatic concordance in 26 of the 33 cases &#40;79&#37;&#41;&#46; Five discordant cases were <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">M</span> primary tumors paired with <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">WT</span> metastases&#44; and 2 were <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">WT</span> primary tumors paired with <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">M</span> metastases&#46; Akslen<span class="elsevierStyleHsp" style=""></span>et<span class="elsevierStyleHsp" style=""></span>al&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">52</span></a> studied 18 cases and were able to report results for 17 pairs&#46; Only 2 pairs&#44; both <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">WT</span> primary tumors&#44; were discordant&#46; Busam<span class="elsevierStyleHsp" style=""></span>et<span class="elsevierStyleHsp" style=""></span>al&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">53</span></a> studied cases in which mutation status results obtained by sequencing were available for comparison with the results of immunohistochemical staining for VE1 protein expression&#46; Among them was a <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">M</span> primary tumor with concordant metastasis&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">However&#44; when even smaller samples were studied&#44; the authors saw higher proportions of discordance&#46; Houben<span class="elsevierStyleHsp" style=""></span>et<span class="elsevierStyleHsp" style=""></span>al&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">54</span></a> studied <span class="elsevierStyleItalic">NRAS</span> and <span class="elsevierStyleItalic">BRAF</span> status in 24 pairs&#44; finding 7 cases of primary&#8211;metastatic discordance&#46; Three were in <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">WT</span> primary tumors with <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">M</span> &#40;V600E&#44; V600R&#44; and V600K&#41; metastases&#46; Another 2 cases were in mutant <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">V600E</span> primary tumors with <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">WT</span> metastases that acquired <span class="elsevierStyleItalic">NRAS</span> mutations&#44; which had not been present in the primary tumor&#46; The remaining two cases had only NRAS mutation discordance&#46; Yancovitz<span class="elsevierStyleHsp" style=""></span>et<span class="elsevierStyleHsp" style=""></span>al&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">21</span></a> studied concordance in 18 primary tumors with <span class="elsevierStyleItalic">BRAF</span> and their corresponding metastases&#46; The 8 discordant cases were in 6 <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">WT</span> primary tumors with <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">M</span> metastases&#44; plus 2 <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">M</span> primary tumors with <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">WT</span> metastases&#46; The mutation status of 9 of the primary tumors was heterogeneous&#44; with more than a single cell population within the same tumor&#44; a phenomenon that has been described by other authors&#46;<a class="elsevierStyleCrossRefs" href="#bib0570"><span class="elsevierStyleSup">55&#44;56</span></a> Shinozaki<span class="elsevierStyleHsp" style=""></span>et<span class="elsevierStyleHsp" style=""></span>al&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">19</span></a> detected primary&#8211;metastatic discordance in 8 out of 13 cases&#46; All were <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">WT</span> primary tumors with <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">M</span> metastases&#46; The authors suggested the mutations might have been acquired during disease progression&#46; Finally&#44; the selection of <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">M</span> alleles during the progression of initially heterogeneous primary tumors was observed by Lin<span class="elsevierStyleHsp" style=""></span>et<span class="elsevierStyleHsp" style=""></span>al&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">20</span></a> in samples from 3 patients&#46; In 1 of the cases&#44; the mutation was found on recurrence of a primary tumor that had not initially been positive for the mutation&#46; In another case&#44; the primary tumor was heterogeneous &#40;<span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">WT</span> plus <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">V600K</span>&#41; and 7 of the 9 visceral and subcutaneous metastases showed a predominance of <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">V600K</span>&#46; The third patient had a primary tumor in which <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">V600K</span> was present&#44; but node metastases contained more of mutated alleles&#46; The authors of this study pointed out that even acral and mucosal melanomas can harbor small <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">M</span> subpopulations in the primary tumor that can later predominate on metastasis&#46;</p><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Concordance in Subsequent Metastasis</span><p id="par0110" class="elsevierStylePara elsevierViewall">Several concordance studies have analyzed DNA sequencing data for several metastases in the same patient even though mutation status for the primary tumor was unavailable&#46; In an interesting study in 15 patients&#44; Sigalotti<span class="elsevierStyleHsp" style=""></span>et<span class="elsevierStyleHsp" style=""></span>al&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">57</span></a> analyzed 15 initial metastases and 19 subsequent metastases&#46; They found that <span class="elsevierStyleItalic">BRAF</span> mutation status &#40;3 <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">WT</span> and 12 <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">M</span>&#41; was maintained in all but 2 cases&#44; in which later metastases from the primary tumors were homozygous although the earlier metastatic tumors had been heterozygous&#46; These observations suggest the stability of established mutation status in metastatic melanoma regardless of location or time frame&#46; Saroufim<span class="elsevierStyleHsp" style=""></span>et<span class="elsevierStyleHsp" style=""></span>al&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">58</span></a> also studied subsequent metastases and Niessner<span class="elsevierStyleHsp" style=""></span>et<span class="elsevierStyleHsp" style=""></span>al&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">59</span></a> studied paired cerebral and extracerebral metastases&#44; finding identical patterns of <span class="elsevierStyleItalic">BRAF</span>&#44; <span class="elsevierStyleItalic">NRAS</span>&#44; and <span class="elsevierStyleItalic">KIT</span> oncogene mutations&#46; In contrast&#44; when Chang<span class="elsevierStyleHsp" style=""></span>et<span class="elsevierStyleHsp" style=""></span>al&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">56</span></a> sequenced DNA in frozen tissue in 3 cases of multiple metastases&#44; they found complete mutation status concordance in only a single case&#46; The other 2 were discordant&#46;</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Discussion</span><p id="par0115" class="elsevierStylePara elsevierViewall">Discordance between primary tumors and their corresponding metastasis can be explained by a theory recently advanced by Yancovitz<span class="elsevierStyleHsp" style=""></span>et<span class="elsevierStyleHsp" style=""></span>al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">21</span></a> according to which different subclone populations can coexist in a single tumor &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#44; a status referred to as intratumoral heterogeneity&#46; The presence of different cell populations&#44; some carrying a mutation and others not&#44; allows both <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">M</span> and <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">WT</span> metastases to develop&#46; Similarly&#44; resistance to targeted therapy as well as disease progression through clonal selection&#44; which has been observed in some patients who initially responded well to BRAFi therapy&#44; can be explained by both intratumoral and intertumoral heterogeneity &#40;presence of different subclones in primary and metastatic tumors&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">The studies in the larger sample sizes suggest that discordance is low or nearly absent in cutaneous melanoma&#46; The findings of discordance in some studies could be attributed to the presence of mutations other than V600E or to the use of a single detection method&#44; as some have low sensitivity&#46; The study with the largest sample size&#44; one which also used the largest number of detection techniques&#44; found 100&#37; concordance&#44;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">50</span></a> supporting the theory that melanoma mutation status stays stable during progression&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">In any case&#44; though the prevalence of discordant metastases may be low&#44; the possibility should not be ignored given that patients with discordant tumors who might be candidates for BRAFi therapy may be affected&#46; Not detecting mutation status might deny them the treatment&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">It therefore seems reasonable to propose that the ideal tissue for mutation status assessment would come from the most recent metastasis&#46; However&#44; when such tissue is unavailable for analysis&#44; the high levels of concordance found in larger studies suggests that mutations in the primary tumor should be studied instead&#46; Similarly&#44; new metastases that occur when progression takes place during BRAFi therapy should be analyzed for clones that do not carry the same mutation&#46; Moreover&#44; combining techniques&#8212;such as RT-qPCR and immunohistochemistry&#8212;would increase detection sensitivity&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Ethical Disclosures</span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Protection of human and animal subjects</span><p id="par0135" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals for this investigation&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Data confidentiality</span><p id="par0140" class="elsevierStylePara elsevierViewall">The authors declare that no private patient data are disclosed in this article&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Right to privacy and informed consent</span><p id="par0145" class="elsevierStylePara elsevierViewall">The authors declare that no private patient data are disclosed in this article&#46;</p></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conflicts of Interest</span><p id="par0150" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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          "identificador" => "xpalclavsec921161"
          "titulo" => "Keywords"
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          "titulo" => "Introduction"
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          "identificador" => "sec0010"
          "titulo" => "BRAF Mutation in Melanoma"
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        6 => array:3 [
          "identificador" => "sec0015"
          "titulo" => "Detecting BRAF Mutations"
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            0 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Sequencing"
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            1 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Real-Time PCR"
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            2 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Anti-VE1 Monoclonal Antibody"
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            3 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "Liquid Biopsy"
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        7 => array:3 [
          "identificador" => "sec0040"
          "titulo" => "Primary&#8211;Metastatic BRAF Mutation Status Concordance"
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              "identificador" => "sec0045"
              "titulo" => "Concordance in Subsequent Metastasis"
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          "titulo" => "Discussion"
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              "titulo" => "Protection of human and animal subjects"
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              "identificador" => "sec0065"
              "titulo" => "Data confidentiality"
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              "identificador" => "sec0070"
              "titulo" => "Right to privacy and informed consent"
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          "identificador" => "sec0075"
          "titulo" => "Conflicts of Interest"
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        11 => array:1 [
          "titulo" => "References"
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    "fechaRecibido" => "2016-09-29"
    "fechaAceptado" => "2016-12-31"
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          "clase" => "keyword"
          "titulo" => "Keywords"
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          "palabras" => array:5 [
            0 => "Melanoma"
            1 => "Concordance"
            2 => "Metastasis"
            3 => "BRAF"
            4 => "Intratumoral heterogeneity"
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          "titulo" => "Palabras clave"
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            0 => "Melanoma"
            1 => "Concordancia"
            2 => "Met&#225;stasis"
            3 => "BRAF"
            4 => "Heterogeneidad intratumoral"
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        ]
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The identification of B-Raf proto-oncongene &#40;<span class="elsevierStyleItalic">BRAF</span>&#41; mutation and the emergence of targeted therapy marked a turning point in the treatment of melanoma&#46; The study of mutation status concordance between primary tumors and metastases in this cancer has major treatment implications as it facilitates the selection of candidates for targeted therapy&#46; This review analyzes the evidence on the level of mutation status concordance between primary tumors and different types of metastases in cutaneous melanoma and provides an overview of the advantages and disadvantages of the various methods used to detect <span class="elsevierStyleItalic">BRAF</span> mutations&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La mutaci&#243;n en el oncog&#233;n BRAF en melanoma y la aparici&#243;n de terapias dirigidas frente a ella han supuesto un antes y un despu&#233;s en el tratamiento de esta enfermedad&#46; El estudio del estado mutacional en las met&#225;stasis y su concordancia con el tumor primario tiene adem&#225;s una gran implicaci&#243;n terap&#233;utica en estos pacientes&#44; pues permite seleccionar candidatos a estos tratamientos&#46; El objetivo de esta revisi&#243;n es conocer las evidencias disponibles sobre el grado de concordancia en los distintos tipos de met&#225;stasis en el melanoma cut&#225;neo&#44; as&#237; como las ventajas y desventajas de los distintos m&#233;todos de detecci&#243;n de la mutaci&#243;n en BRAF&#46;</p></span>"
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      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as&#58; Godoy-Gij&#243;n E&#44; Yuste-Chaves M&#44; Santos-Briz &#193;&#46; Concordancia mutacional de BRAF entre melanoma primario cut&#225;neo y sus correspondientes met&#225;stasis&#46; Revisi&#243;n de la evidencia actual&#46; Actas Dermosifiliogr&#46; 2017&#59;108&#58;894&#8211;901&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Example of a pyrogram&#46;</p>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Real-time quantitative reverse transcription polymerase chain reaction to detect mutations in <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">V600</span>&#46; A&#44; DNA study of a tumor without the <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">V600E</span> mutation&#46; Binding with a single probe &#40;for WT&#41; resulted in a single fluorescence signal interpreted to indicate &#8220;not mutated&#46;&#8221; B&#44; DNA study of a tumor with the <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">V600E</span> mutation&#46; Binding with 2 probes resulted in emission of 2 types of fluorescence to indicate &#8220;mutated&#46;&#8221; WT refers to wild-type&#59; Pol&#44; DNA polymerase enzymes&#59; qPCR&#44; quantitative polymerase chain reaction&#46;</p> <p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Source&#58; Adapted from Curry et al&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">30</span></a></p>"
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Intratumoral heterogeneity&#46; Presence in a single tumor of subclones carrying the <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">V600E</span> mutation in a mainly <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">WT</span> primary tumor&#46;</p>"
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          "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; Conc&#44; concordance&#59; Disc&#44; discordance&#59; IH&#44; immunohistochemistry&#59; PCR&#44; polymerase chain reaction&#59; SS&#44; Sanger sequencing&#59; BRAF&#44; B-Raf proto-oncogene&#59; M &#40;superscript&#41;&#44; mutant&#59; WT &#40;superscript&#41;&#44; wild-type&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">N&#44; Primary Tumor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">N&#44; Metastatis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="3" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Lymphatic</th><th class="td" title="table-head  " colspan="3" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Soft-Tissue</th><th class="td" title="table-head  " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Visceral</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Method&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Discordance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">N&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Conc&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Disc&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">N&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Conc&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Disc&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">N&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Conc&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Disc&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Riveiro et al&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">50</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">140&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">171&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">100&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">100 &#40;100&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">62&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">62 &#40;100&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9 &#40;100&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PCR<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>IH<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Colombino et al&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">17</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">102&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">165&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">84&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">78 &#40;93&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6 &#40;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">36&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">29 &#40;81&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7 &#40;19&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">45&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">43 &#40;96&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">M</span>&#47;<span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">WT</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Saroufim et al&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">51</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20 &#40;91&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;9&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4 &#40;57&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 &#40;43&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;50&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;50&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PCR<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>IH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">M</span>&#47;<span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">WT</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Shinozaki et al&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">19</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7 &#40;58&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 &#40;42&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 &#40;100&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">WT</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Lin et al&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">20</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;40&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 &#40;60&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;100&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 &#40;33&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;67&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">M</span>&#47;<span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">WT</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="14" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Omholt et al&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">18</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">71&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">51<span class="elsevierStyleSup">b</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">49 &#40;96&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">WT</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Houben et al&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">54</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">24<span class="elsevierStyleSup">b</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">19 &#40;79&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 &#40;21&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">M</span>&#47;<span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">WT</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Akslen et al&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">52</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">17<span class="elsevierStyleSup">b</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15 &#40;88&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;12&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">WT</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Yancovitz et al&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">21</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">18<span class="elsevierStyleSup">b</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10 &#40;56&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8 &#40;44&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SS<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>PCR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">M</span>&#47;<span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">WT</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Busam et al&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">53</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1<span class="elsevierStyleSup">b</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 &#40;100&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SS<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>IH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1607259.png"
              ]
            ]
          ]
          "notaPie" => array:1 [
            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Type of metastasis was specified by the first 5 author groups&#59; the second 5 groups did not specify type&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Primary&#8211;Metastatic <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">V600</span> Mutation Status Concordance in the Literature <a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a></p>"
        ]
      ]
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Article information

ISSN: 15782190
Original language: English

DOI:10.1016/j.adengl.2017.10.002

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	8	12	20
2024 October	70	37	107
2024 September	71	16	87
2024 August	115	54	169
2024 July	75	26	101
2024 June	91	37	128
2024 May	88	31	119
2024 April	88	17	105
2024 March	85	27	112
2024 February	82	34	116
2024 January	69	36	105
2023 December	61	12	73
2023 November	71	27	98
2023 October	79	38	117
2023 September	65	28	93
2023 August	60	22	82
2023 July	64	33	97
2023 June	55	23	78
2023 May	72	25	97
2023 April	59	20	79
2023 March	80	21	101
2023 February	51	32	83
2023 January	42	41	83
2022 December	66	35	101
2022 November	53	26	79
2022 October	51	25	76
2022 September	36	47	83
2022 August	31	30	61
2022 July	36	43	79
2022 June	47	26	73
2022 May	54	45	99
2022 April	84	37	121
2022 March	81	51	132
2022 February	61	37	98
2022 January	61	46	107
2021 December	49	48	97
2021 November	86	54	140
2021 October	92	67	159
2021 September	64	42	106
2021 August	46	36	82
2021 July	41	25	66
2021 June	55	42	97
2021 May	38	43	81
2021 April	74	62	136
2021 March	62	35	97
2021 February	60	28	88
2021 January	27	16	43
2020 December	27	19	46
2020 November	39	24	63
2020 October	30	10	40
2020 September	39	11	50
2020 August	23	16	39
2020 July	29	15	44
2020 June	29	23	52
2020 May	23	14	37
2020 April	34	23	57
2020 March	28	19	47
2020 February	5	0	5
2020 January	2	0	2
2019 December	4	0	4
2019 November	4	0	4
2019 September	5	0	5
2019 August	8	0	8
2019 July	4	0	4
2019 June	4	0	4
2019 May	4	1	5
2019 April	3	0	3
2019 March	2	0	2
2019 February	3	0	3
2018 December	4	0	4
2018 November	4	0	4
2018 October	2	0	2
2018 September	2	0	2
2018 March	0	1	1
2018 February	39	8	47
2018 January	124	11	135
2017 December	75	42	117
2017 November	11	13	24

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