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BRAF en c&#225;ncer de colon &#40;98-100&#37; de concordancia&#41;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">2&#8211;5</span></a> y KRAS en c&#225;ncer de colon &#40;92-100&#37; concordancia&#41;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">2&#44;3&#44;6&#8211;14</span></a>&#46; Aunque algunos autores han reflejado una tasa de discordancia nada despreciable entre el tumor primario y sus correspondientes met&#225;stasis&#58; HER-2 en c&#225;ncer de es&#243;fago &#40;hasta un 22&#44;5&#37; de discordancia&#41;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">15</span></a> y KRAS en c&#225;ncer de colon &#40;hasta un 32&#44;4&#37;&#41;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">5&#44;16</span></a>&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">En melanoma son pocos los estudios que analizan la correlaci&#243;n mutacional entre la lesi&#243;n primaria y sus met&#225;stasis&#46; Los resultados son heterog&#233;neos&#44; encontrando algunos autores una elevada concordancia<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">17&#44;18</span></a> mientras que otros muestran tasas alrededor del 50&#37;<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">19&#8211;21</span></a>&#46; La mayor parte de estas publicaciones basan sus resultados en un solo m&#233;todo de determinaci&#243;n de la mutaci&#243;n y un tama&#241;o muestral bajo que no permite obtener conclusiones v&#225;lidas&#46; El objetivo de esta publicaci&#243;n es revisar la evidencia cient&#237;fica actual en el melanoma cut&#225;neo respecto a los distintos m&#233;todos de detecci&#243;n de la mutaci&#243;n en BRAF utilizados en la pr&#225;ctica cl&#237;nica y la concordancia mutacional entre el tumor primario y sus correspondientes met&#225;stasis&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">La mutaci&#243;n BRAF en melanoma</span><p id="par0020" class="elsevierStylePara elsevierViewall">La prote&#237;na BRAF es uno de los miembros clave de la v&#237;a de las MAPK&#46; Se encuentra codificada en el oncog&#233;n BRAF en el cromosoma 7q34<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">22</span></a>&#46; De entre las mutaciones en el gen BRAF&#44; la mutaci&#243;n en un nucle&#243;tido en el cod&#243;n 600 &#40;V600E&#41; en el ex&#243;n 15 causante de la sustituci&#243;n de valina por &#225;cido glut&#225;mico &#40;GTG<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>GAG&#41; en la prote&#237;na es la m&#225;s frecuente&#44; ocurriendo hasta en el 85-90&#37; de los casos<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">22&#8211;24</span></a>&#46; La segunda mutaci&#243;n en frecuencia &#40;V600K&#41; es la que da lugar a la sustituci&#243;n de valina por lisina &#40;GTG<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>AAG&#41; con hasta un 20-21&#37; de los casos mutados<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">25&#8211;28</span></a>&#44; habi&#233;ndose registrado una mayor prevalencia en algunas poblaciones<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">25&#44;28</span></a>&#46; Otras mutaciones como 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 y D594N son m&#225;s infrecuentes<a class="elsevierStyleCrossRefs" href="#bib0440"><span class="elsevierStyleSup">29&#44;30</span></a>&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">La alteraci&#243;n en la prote&#237;na BRAF produce una activaci&#243;n constitutiva de la v&#237;a de las MAPK&#44; evitando as&#237; la necesidad de activaci&#243;n por parte de RAS&#46; Su mutaci&#243;n genera una actividad quinasa de la prote&#237;na 10 veces superior a la forma no mutada &#40;BRAF<span class="elsevierStyleSup">WT</span>&#41;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">22&#44;31</span></a>&#44; conduciendo a la proliferaci&#243;n neopl&#225;sica mediada por una transcripci&#243;n continuada&#46; La mutaci&#243;n som&#225;tica en el oncog&#233;n BRAF est&#225; presente con mayor frecuencia en el melanoma cut&#225;neo que en otros tumores<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">22</span></a>&#46; Por otro lado&#44; esta mutaci&#243;n est&#225; presente en hasta el 50-70&#37; de los melanomas&#44; siendo con diferencia la mutaci&#243;n m&#225;s frecuente en el melanoma cut&#225;neo respecto a otras como NRAS&#44; p16 o p53<a class="elsevierStyleCrossRefs" href="#bib0455"><span class="elsevierStyleSup">32&#44;33</span></a>&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos de detecci&#243;n de las mutaciones en BRAF</span><p id="par0030" class="elsevierStylePara elsevierViewall">Existen distintos m&#233;todos que permiten la detecci&#243;n de las mutaciones en BRAF&#46; La elecci&#243;n de uno u otro m&#233;todo se ve justificada por su facilidad&#47;rapidez de realizaci&#243;n&#44; su sensibilidad&#47;especificidad&#44; as&#237; como por su coste&#46;</p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Secuenciaci&#243;n</span><p id="par0035" class="elsevierStylePara elsevierViewall">La secuenciaci&#243;n de Sanger y la pirosecuenciaci&#243;n son los m&#233;todos para determinar el estado mutacional utilizados m&#225;s ampliamente en investigaci&#243;n&#46; Durante a&#241;os la secuenciaci&#243;n de Sanger de ADN previamente amplificado mediante la reacci&#243;n en cadena de la polimerasa &#40;PCR&#41; se ha considerado el m&#233;todo de referencia para la detecci&#243;n de mutaciones adquiridas en tumores y para la secuenciaci&#243;n del genoma humano&#46; Se trata de una t&#233;cnica que permite detectar sustituciones de bases&#44; deleciones e inserciones&#44; aunque no alteraciones en las copias cromos&#243;micas o translocaciones<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">30</span></a>&#46; Este tipo de secuenciaci&#243;n precisa de un tiempo elevado para su realizaci&#243;n &#40;18-19<span class="elsevierStyleHsp" style=""></span>h&#41;&#44; un equipo espec&#237;fico no siempre disponible en muchos laboratorios y un personal cualificado para la lectura de los resultados&#46; Posee una alta especificidad&#44; pero su mayor limitaci&#243;n es que posee una baja sensibilidad &#40;92&#44;5&#37;&#41;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">34</span></a>&#44; lo cual obliga a disponer de una carga tumoral de hasta un 5&#37; en las muestras a analizar<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">30</span></a>&#46; Su tasa superior de falsos negativos condiciona un mayor riesgo de que pacientes portadores de la mutaci&#243;n no sean tratados con los BRAFi&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">La pirosecuenciaci&#243;n o secuenciaci&#243;n por s&#237;ntesis se basa en la liberaci&#243;n de pirofosfato por la ADN polimerasa al a&#241;adir nucle&#243;tidos de forma complementaria a la cadena de ADNss&#46; Para su realizaci&#243;n se realiza una amplificaci&#243;n del ADN mediante PCR&#44; se hibrida la cadena de ADNss con un <span class="elsevierStyleItalic">primer</span> y finalmente se incuba con las enzimas&#46; Posteriormente se a&#241;aden y lavan secuencialmente soluciones con los nucle&#243;tidos A&#44; C&#44; G y T&#46; El pirofosfato liberado con la incorporaci&#243;n de un nucle&#243;tido se acopla a las enzimas ATP sulfurilasa y luciferasa para generar luz detectable mediante una reacci&#243;n de quimioluminiscencia&#46; La liberaci&#243;n de luz producida es detectada cada vez que una base es a&#241;adida&#44; y la se&#241;al queda registrada como un pico en un gr&#225;fico llamado pirograma &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>&#41;&#46; La intensidad de la luz representada por la altura de dicho pico determinar&#225; si hay m&#225;s de un nucle&#243;tido repetido<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">35&#44;36</span></a>&#46; Esta t&#233;cnica permite detectar no solo la presencia o ausencia de mutaci&#243;n&#44; sino tambi&#233;n el porcentaje de ADN que porta la mutaci&#243;n&#46; La pirosecuenciaci&#243;n ha mostrado una sensibilidad muy superior a la secuenciaci&#243;n de Sanger<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">30</span></a>&#44; detectando tambi&#233;n no solo la mutaci&#243;n BRAF<span class="elsevierStyleSup">V600E</span>&#44; sino tambi&#233;n otras mutaciones menos frecuentes como V600K&#44; V600D&#44; V600R&#44; K601E<a class="elsevierStyleCrossRefs" href="#bib0445"><span class="elsevierStyleSup">30&#44;34</span></a>&#46; Se trata de una t&#233;cnica r&#225;pida &#40;&#60;<span class="elsevierStyleHsp" style=""></span>24<span class="elsevierStyleHsp" style=""></span>h&#41; pero que&#44; con frecuencia&#44; produce errores en secuencias con un mismo nucle&#243;tido repetido 6-7 veces &#40;homopol&#237;meros&#41;&#46; A diferencia de la secuenciaci&#243;n de Sanger&#44; que permite detectar longitudes de 800-1000 nucle&#243;tidos&#44; esta t&#233;cnica permite solo detectar 300-500 nucle&#243;tidos&#46; La mayor desventaja es el coste elevado de los reactantes y la necesidad de un equipo espec&#237;fico&#44; no siempre disponible en los laboratorios convencionales&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Reacci&#243;n en cadena de la polimerasa a tiempo real</span><p id="par0045" class="elsevierStylePara elsevierViewall">Las pruebas diagn&#243;sticas basadas en reacci&#243;n en cadena de la polimerasa a tiempo real &#40;RT-qPCR&#41; se han convertido en el m&#233;todo m&#225;s utilizado en los laboratorios cl&#237;nicos para la detecci&#243;n de mutaciones en tejido tumoral&#46; Se trata de una t&#233;cnica m&#225;s r&#225;pida &#40;&#60;<span class="elsevierStyleHsp" style=""></span>8<span class="elsevierStyleHsp" style=""></span>h&#41; y con sensibilidad superior a la secuenciaci&#243;n de Sanger de hasta un 97&#44;5&#37;<a class="elsevierStyleCrossRefs" href="#bib0465"><span class="elsevierStyleSup">34&#44;37&#44;38</span></a>&#46; La t&#233;cnica <span class="elsevierStyleItalic">in vitro</span> se basa en el uso de un termociclador incorporando un lector de fluorescencia &#40;<a class="elsevierStyleCrossRef" href="#fig0010">fig&#46; 2</a>&#41;&#46; El objetivo es la detecci&#243;n mediante fluorescencia de la mutaci&#243;n presente en ADN extra&#237;do de muestras tisulares fijadas en formalina y embebidas en parafina&#46; En el caso de la mutaci&#243;n en el protooncog&#233;n BRAF el estudio se dirige hacia una secuencia espec&#237;fica en el ex&#243;n 15&#46; El resultado nos permite conocer la presencia o ausencia de mutaci&#243;n&#46; Se trata&#44; por tanto&#44; de una t&#233;cnica r&#225;pida y econ&#243;mica&#44; que permite analizar lotes de 3 muestras sin reducci&#243;n del rendimiento del reactivo y la utilizaci&#243;n de dispositivos ya presentes en el laboratorio para la detecci&#243;n de otras mutaciones solicitadas en la pr&#225;ctica cl&#237;nica diaria &#40;como KRAS en c&#225;ncer de colon o EGFR en carcinoma de pulm&#243;n no microc&#237;tico&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">Actualmente se encuentran aprobados varios dispositivos para la realizaci&#243;n de RT-qPCR&#44; siendo la plataforma Cobas&#174; 4800 BRAF V600 Mutation Test &#40;Roche Molecular Systems&#41; la m&#225;s ampliamente utilizada tras su aprobaci&#243;n en 2011 por la FDA para pacientes candidatos a tratamiento con vemurafenib&#46; La utilidad cl&#237;nica del test Cobas&#174; ha sido validada para la identificaci&#243;n de tumores portadores de la mutaci&#243;n BRAF<span class="elsevierStyleSup">V600E</span> &#40;100&#37; de las muestras detectadas&#41;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">39</span></a>&#44; mostr&#225;ndose tambi&#233;n de utilidad para la determinaci&#243;n de las mutaciones BRAF<span class="elsevierStyleSup">V600K</span> &#40;70&#37; de las muestras detectadas&#41;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">39</span></a>&#44; BRAF<span class="elsevierStyleSup">V600D</span> y BRAF<span class="elsevierStyleSup">V600E2</span><a class="elsevierStyleCrossRefs" href="#bib0485"><span class="elsevierStyleSup">38&#44;40</span></a>&#46; El l&#237;mite inferior de detecci&#243;n de la mutaci&#243;n con la plataforma Cobas&#174; es de 4&#44;4&#37; alelos mutados por 1&#44;25<span class="elsevierStyleHsp" style=""></span>ng&#47;&#956;l&#46; En el caso de mutaciones como la V600K y V600E2 se requieren porcentajes m&#225;s elevados &#40;31&#37; y 68&#37; respectivamente&#41;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">30</span></a>&#46; Los errores objetivados con esta t&#233;cnica frecuentemente se deben al pigmento mel&#225;nico&#44; considerado un inhibidor de la PCR&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Yancovitz et al&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">21</span></a> determinaron la presencia de la mutaci&#243;n BRAF<span class="elsevierStyleSup">V600E</span> con esta t&#233;cnica en 112 muestras de melanoma hallando una positividad en el 75&#44;9&#37; &#40;66&#44;7&#37; primarios y 77&#44;7&#37; met&#225;stasis&#41; frente a la obtenida mediante secuenciaci&#243;n convencional en las mismas muestras del 32&#44;1&#37; de los casos &#40;38&#44;9&#37; primarios y 30&#44;9&#37; met&#225;stasis&#41;&#46; En estos casos&#44; adem&#225;s&#44; no hallaron ning&#250;n tumor mutado que fuese detectado por la secuenciaci&#243;n&#44; pero no por la PCR a tiempo real&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">En el caso de las muestras citol&#243;gicas obtenidas por punci&#243;n algunos autores<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">41</span></a> han mostrado tambi&#233;n la utilidad de este m&#233;todo para su estudio&#46; Se ha hallado una concordancia del 93&#37; con respecto a la secuenciaci&#243;n en 117 muestras parafinadas y citol&#243;gicas&#44; conteniendo estas &#250;ltimas al menos un 50&#37; de c&#233;lulas tumorales&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Anticuerpo monoclonal VE1</span><p id="par0065" class="elsevierStylePara elsevierViewall">Recientemente se ha desarrollado un anticuerpo monoclonal frente a la prote&#237;na mutada BRAF<span class="elsevierStyleSup">V600E</span> &#40;VE1&#41;<a class="elsevierStyleCrossRefs" href="#bib0505"><span class="elsevierStyleSup">42&#8211;44</span></a>&#46; Este anticuerpo permite la detecci&#243;n de la mutaci&#243;n mediante t&#233;cnicas inmunohistoqu&#237;micas en muestras parafinadas de los tumores&#46; La t&#233;cnica ha mostrado una sensibilidad de hasta el 100&#37;<a class="elsevierStyleCrossRefs" href="#bib0465"><span class="elsevierStyleSup">34&#44;45</span></a> en la detecci&#243;n de la mutaci&#243;n BRAF<span class="elsevierStyleSup">V600E</span>&#44; aunque no permite detectar otras mutaciones incluyendo la BRAF<span class="elsevierStyleSup">V600K</span>&#46; Dado que la inmunohistoqu&#237;mica es una t&#233;cnica r&#225;pida y econ&#243;mica utilizada rutinariamente en el laboratorio anatomopatol&#243;gico hospitalario&#44; su aplicaci&#243;n se muestra como una herramienta r&#225;pida y eficiente para la pr&#225;ctica cl&#237;nica diaria&#46; El problema es que se trata de un m&#233;todo no aprobado por el momento por la FDA o la EMEA para la detecci&#243;n de la mutaci&#243;n en pacientes candidatos a tratamiento con BRAFi&#46; Por otro lado&#44; teniendo en cuenta que los BRAFi se han mostrado eficaces en el tratamiento de tumores con la mutaci&#243;n BRAF<span class="elsevierStyleSup">V600K</span>&#44; la utilizaci&#243;n de la inmunohistoqu&#237;mica como t&#233;cnica de detecci&#243;n exclusivamente impedir&#237;a que los pacientes con dicha mutaci&#243;n se beneficiasen del tratamiento&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Biopsia l&#237;quida</span><p id="par0070" class="elsevierStylePara elsevierViewall">La llamada &#171;biopsia l&#237;quida&#187; es una t&#233;cnica que ha sido estudiada en otros tumores s&#243;lidos<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">46</span></a> y est&#225; adquiriendo cada vez m&#225;s relevancia en melanoma&#46; Este t&#233;rmino abarca tanto la detecci&#243;n en sangre perif&#233;rica de c&#233;lulas tumorales circulantes&#44; como de ADN tumoral circulante &#40;ctADN&#41; o de microARN circulantes<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">47</span></a>&#46; El estudio en plasma mediante RT-qPCR tanto de c&#233;lulas tumorales circulantes como de ADN tumoral circulante liberado tras la apoptosis o necrosis celular supone un campo prometedor en el seguimiento de los pacientes con melanoma metast&#225;sico&#46; Actualmente se encuentra en validaci&#243;n su utilidad no solo en la existencia de discordancia mutacional con el tumor primario&#44; sino tambi&#233;n en la valoraci&#243;n de la respuesta a tratamientos y la reca&#237;da tumoral&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Parece razonable&#44; por tanto&#44; la utilizaci&#243;n combinada de t&#233;cnicas como la inmunohistoqu&#237;mica con t&#233;cnicas moleculares como la RT-qPCR o la pirosecuenciaci&#243;n para la detecci&#243;n de la mutaci&#243;n BRAF en pacientes con melanoma metast&#225;sico&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Concordancia mutacional de BRAF entre el tumor primario y las met&#225;stasis</span><p id="par0080" class="elsevierStylePara elsevierViewall">Dado que la discordancia entre el estado mutacional del tumor primario y las met&#225;stasis ya ha sido objetivada en otros tumores<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">48</span></a>&#44; y esta constituye una causa de resistencia al tratamiento&#44; su estudio resulta esencial para pacientes oncol&#243;gicos candidatos a terapias dirigidas&#46; En el melanoma metast&#225;sico el estudio de otras mutaciones&#44; como NRAS&#44; ha mostrado una concordancia elevada<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">49</span></a>&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Si revisamos los estudios publicados hasta la fecha sobre concordancia mutacional de BRAF en melanoma podremos objetivar que la mayor&#237;a de ellos han sido realizados con un bajo tama&#241;o muestral<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">19&#8211;21</span></a>&#46; Son una excepci&#243;n a ello los publicados por Colombino et al&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">17</span></a> y&#44; m&#225;s recientemente&#44; por nuestro grupo<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">50</span></a>&#46; Si revisamos las tasas de concordancia en los estudios publicados podemos evidenciar que muestran resultados dispares &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">tabla 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">Colombino et al&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">17</span></a> encuentran una baja tasa de discordancia &#40;15 de 165 casos&#41;&#44; siendo las lesiones discordantes un 53&#37; tumores primarios BRAF<span class="elsevierStyleSup">WT</span> con met&#225;stasis BRAF<span class="elsevierStyleSup">M</span> y un 47&#37; tumores primarios BRAF<span class="elsevierStyleSup">M</span> con met&#225;stasis BRAF<span class="elsevierStyleSup">WT</span>&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Nuestro grupo<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">50</span></a>&#44; en un estudio multic&#233;ntrico con un tama&#241;o muestral mayor que incluye 140 melanomas primarios y 171 met&#225;stasis emparejadas&#44; obtiene una tasa mayor de concordancia&#46; Dicha tasa es del 83&#44;6&#37; cuando se determina la mutaci&#243;n con la plataforma Cobas<span class="elsevierStyleSup">&#174;</span> y asciende hasta el 100&#37; de concordancia cuando se combinan la RT-qPCR con la secuenciaci&#243;n y la inmunohistoqu&#237;mica VE1&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Otros autores&#44; con un tama&#241;o muestral menor&#44; obtienen tambi&#233;n elevadas tasas de concordancia&#46; Omholt et al&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">18</span></a> estudian BRAF en 71 melanomas primarios de los que en 51 casos pueden estudiarse met&#225;stasis emparejadas &#40;aunque sin especificar en el estudio el tipo de met&#225;stasis&#41;&#46; Solo 2 casos presentan discordancia&#44; siendo tumores primarios BRAF<span class="elsevierStyleSup">WT</span> con met&#225;stasis BRAF<span class="elsevierStyleSup">M</span>&#46; En 17 casos estudian adem&#225;s met&#225;stasis consecutivas&#44; encontrando solo un caso discordante de un paciente con primario BRAF<span class="elsevierStyleSup">M</span> que desarroll&#243; posteriormente una met&#225;stasis BRAF<span class="elsevierStyleSup">M</span> y otra BRAF<span class="elsevierStyleSup">WT</span>&#46; Saroufim et al&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">51</span></a> estudian 40 muestras de tumores primarios y met&#225;stasis emparejadas&#44; de las cuales solo se dispone de tejido suficiente en 33&#46; En 6 casos obtienen resultados no valorables con RT-qPCR&#44; por lo que recurren a la inmunohistoqu&#237;mica&#46; Objetivan una concordancia en 26 casos &#40;79&#37;&#41;&#44; siendo los casos discordantes 5 tumores primarios BRAF<span class="elsevierStyleSup">M</span> con met&#225;stasis BRAF<span class="elsevierStyleSup">WT</span> y 2 primarios BRAF<span class="elsevierStyleSup">WT</span> con met&#225;stasis BRAF<span class="elsevierStyleSup">M</span>&#46; Akslen et al&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">52</span></a> estudian 18 casos&#44; de ellos en 17 obtienen resultados mostrando solo 2 casos discordantes&#44; siendo ambos casos tumores primarios BRAF<span class="elsevierStyleSup">WT</span>&#46; Busam et al&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">53</span></a> realizan un estudio con muestras de pacientes con estado mutacional ya conocido por secuenciaci&#243;n en las que valoran los resultados de la tinci&#243;n inmunohistoqu&#237;mica VE1&#46; Entre los casos se encuentra un tumor primario BRAF<span class="elsevierStyleSup">M</span> en el que se valora su correspondiente met&#225;stasis&#44; que muestra concordancia&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Estudios con un bajo tama&#241;o muestral evidencian en cambio una mayor discordancia&#46; Houben et al&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">54</span></a> estudian NRAS y BRAF en una muestra de 24 met&#225;stasis emparejadas&#44; encontrando discordancia en 7 casos&#46; En 3 casos se trata de tumores primarios BRAF<span class="elsevierStyleSup">WT</span> que presentan met&#225;stasis BRAF<span class="elsevierStyleSup">M</span> &#40;V600E&#44; V600R&#44; V600<span class="elsevierStyleHsp" style=""></span>K&#41;&#46; Otros 2 casos son tumores inicialmente mutados &#40;BRAF<span class="elsevierStyleSup">V600E</span>&#41; cuyas met&#225;stasis son BRAF<span class="elsevierStyleSup">WT</span>&#44; pero adquieren mutaciones en NRAS que no estaban presentes en el tumor primario&#46; El resto de los casos muestran discordancia mutacional exclusivamente en NRAS&#46; Yancovitz et al&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">21</span></a> estudian la concordancia de BRAF en 18 tumores y sus correspondientes met&#225;stasis&#46; De los 8 casos discordantes&#44; 6 son tumores BRAF<span class="elsevierStyleSup">WT</span> con met&#225;stasis BRAF<span class="elsevierStyleSup">M</span>&#44; mientras que 2 son tumores BRAF<span class="elsevierStyleSup">M</span> con met&#225;stasis BRAF<span class="elsevierStyleSup">WT</span>&#46; Adem&#225;s&#44; objetivan en 9 de los tumores primarios la presencia de heterogeneidad en el estado mutacional de las poblaciones celulares dentro del mismo tumor&#46; Este fen&#243;meno ha sido descrito tambi&#233;n por otros autores<a class="elsevierStyleCrossRefs" href="#bib0570"><span class="elsevierStyleSup">55&#44;56</span></a>&#46; Shinozaki et al&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">19</span></a> encuentran discordancia en 8 casos de 13 estudiados&#44; siendo todos los casos tumores primarios BRAF<span class="elsevierStyleSup">WT</span> que presentan met&#225;stasis BRAF<span class="elsevierStyleSup">M</span>&#46; Los autores indican que la presencia de la mutaci&#243;n podr&#237;a adquirirse durante la progresi&#243;n de la enfermedad&#46; Lin et al&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">20</span></a> objetivan discordancia en muestras de 3 pacientes en los que las poblaciones celulares BRAF<span class="elsevierStyleSup">M</span> en tumores primarios inicialmente heterog&#233;neos se seleccionan positivamente&#46; Una de ellas se trataba de una recurrencia mutada en un paciente con un tumor primario originariamente no portador de la mutaci&#243;n&#46; En otra de las muestras se objetiva heterogeneidad tumoral en el tumor primario &#40;BRAF<span class="elsevierStyleSup">WT</span> &#43;BRAF<span class="elsevierStyleSup">V600K</span>&#41; y una predominancia de la mutaci&#243;n BRAF<span class="elsevierStyleSup">V600K</span> en 7 de las 9 met&#225;stasis viscerales y subcut&#225;neas&#46; Finalmente&#44; un tercer paciente con tumor primario portador de la mutaci&#243;n BRAF<span class="elsevierStyleSup">V600K</span> presenta un mayor n&#250;mero de alelos mutados en la met&#225;stasis ganglionar&#46; Apuntan dichos autores que incluso en melanomas acrales y mucosos pueden hallarse peque&#241;as subpoblaciones minoritarias con mutaci&#243;n en BRAF en el tumor primario que posteriormente predominen en las met&#225;stasis&#46;</p><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Concordancia en met&#225;stasis subsecuentes</span><p id="par0110" class="elsevierStylePara elsevierViewall">Son varios los estudios en los que no se dispone del tumor primario pero s&#237; de varias met&#225;stasis de un mismo paciente para analizar la concordancia&#46; Un estudio interesante es el de Sigalotti et al&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">57</span></a> que analiza met&#225;stasis iniciales &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>15&#41; y subsecuentes &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>19&#41; de 15 pacientes&#46; Encuentran que en todos los casos se manten&#237;a el estado mutacional de BRAF &#40;3 BRAF<span class="elsevierStyleSup">WT</span> y 12 BRAF<span class="elsevierStyleSup">M</span>&#41;&#44; siendo la &#250;nica variaci&#243;n objetivada la adquisici&#243;n en 2 casos de un estatus homozigoto en las met&#225;stasis subsecuentes originadas por lesiones primarias heterozigotas&#46; Este estudio sugiere la estabilidad del estado mutacional del melanoma tras haber alcanzado el estado metast&#225;sico&#44; independientemente de la localizaci&#243;n o intervalo de tiempo transcurrido<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">57</span></a>&#46; Siguiendo esta l&#237;nea&#44; Saroufim et al&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">58</span></a> con met&#225;stasis subsecuentes y Niessner et al&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">59</span></a> con muestras de met&#225;stasis cerebrales y extracerebrales emparejadas&#44; objetivan un patr&#243;n id&#233;ntico en BRAF&#44; NRAS y KIT&#46; En contraposici&#243;n&#44; Chang et al&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">56</span></a> analizan en su estudio 3 casos con met&#225;stasis m&#250;ltiples en tejido criopreservado mediante secuenciaci&#243;n&#44; encontrando concordancia completa en uno de ellos&#44; mientras que en los otros 2 casos encuentran met&#225;stasis discordantes&#46;</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Discusi&#243;n</span><p id="par0115" class="elsevierStylePara elsevierViewall">La existencia de discordancia entre tumores primarios y sus correspondientes met&#225;stasis podr&#237;a explicarse bas&#225;ndose en una reciente teor&#237;a propuesta por Yancovitz et al&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">21</span></a> seg&#250;n la cual en el melanoma existen subclones de distintas poblaciones dentro del mismo tumor &#40;<a class="elsevierStyleCrossRef" href="#fig0015">fig&#46; 3</a>&#41;&#44; la llamada heterogeneidad intratumoral&#46; La presencia de estas distintas poblaciones celulares&#44; unas portadoras de la mutaci&#243;n y otras no&#44; permitir&#237;a el desarrollo tanto de met&#225;stasis BRAF<span class="elsevierStyleSup">M</span> como BRAF<span class="elsevierStyleSup">WT</span>&#46; Del mismo modo&#44; la presencia de heterogeneidad intratumoral &#40;subclones distintos en un mismo tumor&#41; e intertumoral &#40;entre lesiones primarias y sus met&#225;stasis&#41; podr&#237;a explicar la resistencia a las terapias dirigidas y la progresi&#243;n tras una buena respuesta inicial al tratamiento con BRAFi en algunos pacientes por selecci&#243;n clonal&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">Si seleccionamos los estudios con un mayor tama&#241;o muestral&#44; podemos afirmar que la discordancia en el melanoma cut&#225;neo es baja o casi ausente&#46; La existencia de mutaciones distintas de V600E&#44; as&#237; como la utilizaci&#243;n de un solo m&#233;todo de determinaci&#243;n de la mutaci&#243;n&#44; en ocasiones con baja sensibilidad&#44; podr&#237;a explicar gran parte de la discordancia objetivada en algunos estudios&#46; El hecho que el estudio con mayor n&#250;mero de muestras y mayor n&#250;mero de t&#233;cnicas de detecci&#243;n presente un 100&#37; de concordancia apoya la teor&#237;a de una elevada estabilidad en el estado mutacional durante la progresi&#243;n del melanoma&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">En cualquier caso&#44; aunque dicho porcentaje discordante sea bajo&#44; no debe despreciarse teniendo en cuenta que todos los casos discordantes pueden tratarse de pacientes candidatos a beneficiarse del tratamiento con inhibidores de BRAF &#40;BRAFi&#41; y la no detecci&#243;n de la mutaci&#243;n supondr&#237;a negarles dicha opci&#243;n terap&#233;utica&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Parece por tanto l&#243;gico proponer que el tejido id&#243;neo para el an&#225;lisis de la mutaci&#243;n sea el tejido metast&#225;sico disponible m&#225;s reciente&#44; siempre que se disponga de una cantidad adecuada&#46; Cuando no se disponga de acceso a dicho tejido metast&#225;sico&#44; la elevada concordancia de los estudios con mayor tama&#241;o muestral nos indica que ser&#237;a correcto el estudio del tumor primario en su lugar&#46; Del mismo modo&#44; ante una progresi&#243;n durante tratamiento con BRAFi deber&#237;an analizarse las nuevas met&#225;stasis valorando la posible progresi&#243;n por parte de clones no portadores de la mutaci&#243;n&#46; La utilizaci&#243;n adem&#225;s de t&#233;cnicas combinadas&#44; como la RT-qPCR y la inmunohistoqu&#237;mica&#44; permitir&#237;a adem&#225;s aumentar la sensibilidad en la detecci&#243;n de la mutaci&#243;n&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Responsabilidades &#233;ticas</span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Protecci&#243;n de personas y animales</span><p id="par0135" class="elsevierStylePara elsevierViewall">Los autores declaran que para esta investigaci&#243;n no se han realizado experimentos en seres humanos ni en animales&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Confidencialidad de los datos</span><p id="par0140" class="elsevierStylePara elsevierViewall">Los autores declaran que en este art&#237;culo no aparecen datos de pacientes&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Derecho a la privacidad y consentimiento informado</span><p id="par0145" class="elsevierStylePara elsevierViewall">Los autores declaran que en este art&#237;culo no aparecen datos de pacientes&#46;</p></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Conflicto de intereses</span><p id="par0150" class="elsevierStylePara elsevierViewall">Los autores declaran no tener ning&#250;n conflicto de intereses&#46;</p></span></span>"
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          "titulo" => "Introducci&#243;n"
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          "identificador" => "sec0010"
          "titulo" => "La mutaci&#243;n BRAF en melanoma"
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          "titulo" => "M&#233;todos de detecci&#243;n de las mutaciones en BRAF"
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              "titulo" => "Reacci&#243;n en cadena de la polimerasa a tiempo real"
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          "titulo" => "Concordancia mutacional de BRAF entre el tumor primario y las met&#225;stasis"
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              "titulo" => "Confidencialidad de los datos"
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              "titulo" => "Derecho a la privacidad y consentimiento informado"
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    "fechaRecibido" => "2016-09-29"
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            0 => "Melanoma"
            1 => "Concordancia"
            2 => "Met&#225;stasis"
            3 => "BRAF"
            4 => "Heterogeneidad intratumoral"
          ]
        ]
      ]
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
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            0 => "Melanoma"
            1 => "Concordance"
            2 => "Metastasis"
            3 => "BRAF"
            4 => "Intratumoral heterogeneity"
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    "resumen" => array:2 [
      "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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      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0015" class="elsevierStyleSection elsevierViewall"><p id="spar0015" 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>"
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          "es" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Ejemplo de un pirograma&#46;</p>"
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          "es" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">T&#233;cnica de la RT-qPCR para la detecci&#243;n de mutaciones en BRAF V600&#46; A&#46; Estudio de ADN tumoral sin mutaci&#243;n BRAFV600E mostrando c&#243;mo la uni&#243;n con la sonda no mutada &#40;sonda WT&#41; emite una fluorescencia &#250;nica que es interpretada como &#171;NO MUTADO&#187;&#46; B&#46; Estudio de ADN tumoral con mutaci&#243;n BRAFV600E mostrando c&#243;mo la uni&#243;n con ambas sondas emite 2 tipos de fluorescencia que son interpretadas como &#171;MUTADO&#187;&#46;</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Fuente&#58; adaptado de Curry et al&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">30</span></a>&#46;</p>"
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          "es" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Heterogeneidad intratumoral&#46; Presencia de subclones portadores de la mutaci&#243;n BRAFV600E en un tumor primario mayoritariamente BRAFWT&#46;</p>"
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          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Se indican en primer lugar aquellos autores que especifican el tipo de met&#225;stasis y en segundo lugar aquellos que incluyen met&#225;stasis no especificadas&#46;</p><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Conc&#58; concordancia&#59; Disc&#58; discordancia&#59; IH&#58; inmunohistoqu&#237;mica&#59; PCR&#58; reacci&#243;n en cadena de la polimerasa&#59; S&#58; secuenciaci&#243;n Sanger&#46;</p>"
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                  \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="char" valign="top">140&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">171&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">100&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" 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="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">62&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" 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="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" 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>S&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="char" valign="top">102&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">165&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">84&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" 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="char" 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="char" valign="top">36&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" 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="char" 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="char" valign="top">45&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" 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">S&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">BRAF<span class="elsevierStyleSup">M</span>&#47;BRAF<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="char" valign="top">33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" 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="char" 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="char" valign="top">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" 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="char" 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="char" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" 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">BRAF<span class="elsevierStyleSup">M</span>&#47;BRAF<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="char" valign="top">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" 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="char" 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="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" 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">S&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">BRAF<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="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" 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="char" 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="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" 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="char" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" 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">S&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">BRAF<span class="elsevierStyleSup">M</span>&#47;BRAF<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  " 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  " colspan="3" align="center" valign="top"><span class="elsevierStyleBold">No especificadas</span></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="" 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></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="char" valign="top">71&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">51<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&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="char" 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="char" 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">S&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">BRAF<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="char" valign="top">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">24<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&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="char" 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="char" 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">S&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">BRAF<span class="elsevierStyleSup">M</span>&#47;BRAF<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="char" valign="top">17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">17<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&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="char" 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="char" 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">S&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">BRAF<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="char" valign="top">18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">18<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&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="char" 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="char" 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
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