Special Article
The new challenge in oncology: Next-generation sequencing and its application in precision medicine
El nuevo reto en oncología: la secuenciación NGS y su aplicación a la medicina de precisión
Inés Calabriac, Laia Pedrolac, Pablo Berlangaa,b, María José Aparisic, Dolors Sánchez-Izquierdoc, Adela Cañetea,b, José Cerverac,d,e, José María Millánc,d, Victoria Castelb,
Corresponding author
a Unidad de Oncología Pediátrica, Hospital Universitario y Politécnico La Fe, Valencia, Spain
b Investigación Clínica y Traslacional en Cáncer, Instituto de Investigación Sanitaria La Fe, Valencia, Spain
c Unidad Genómica, Instituto de Investigación Sanitaria La Fe, Valencia, Spain
d Unidad Genética, Hospital Universitario y Politécnico La Fe, Valencia, Spain
e Servicio de Hematología, Hospital Universitario y Politécnico La Fe, Valencia, Spain
Read
6700
Timeswas read the article
2705
Total PDF
3995
Total HTML
Share statistics
array:24 [ "pii" => "S2341287916301144" "issn" => "23412879" "doi" => "10.1016/j.anpede.2016.05.002" "estado" => "S300" "fechaPublicacion" => "2016-11-01" "aid" => "2117" "copyright" => "Asociación Española de Pediatría" "copyrightAnyo" => "2016" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "An Pediatr (Barc). 2016;85:273.e1-7" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 2272 "formatos" => array:3 [ "EPUB" => 146 "HTML" => 1430 "PDF" => 696 ] ] "Traduccion" => array:1 [ "es" => array:19 [ "pii" => "S1695403316301990" "issn" => "16954033" "doi" => "10.1016/j.anpedi.2016.05.006" "estado" => "S300" "fechaPublicacion" => "2016-11-01" "aid" => "2117" "copyright" => "Asociación Española de Pediatría" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "An Pediatr (Barc). 2016;85:273.e1-7" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 12730 "formatos" => array:3 [ "EPUB" => 138 "HTML" => 10850 "PDF" => 1742 ] ] "es" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">ARTÍCULO ESPECIAL</span>" "titulo" => "El nuevo reto en oncología: la secuenciación NGS y su aplicación a la medicina de precisión" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "273.e1" "paginaFinal" => "273.e7" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "The new challenge in oncology: Next-generation sequencing and its application in precision medicine" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Inés Calabria, Laia Pedrola, Pablo Berlanga, María José Aparisi, Dolors Sánchez-Izquierdo, Adela Cañete, José Cervera, José María Millán, Victoria Castel" "autores" => array:9 [ 0 => array:2 [ "nombre" => "Inés" "apellidos" => "Calabria" ] 1 => array:2 [ "nombre" => "Laia" "apellidos" => "Pedrola" ] 2 => array:2 [ "nombre" => "Pablo" "apellidos" => "Berlanga" ] 3 => array:2 [ "nombre" => "María José" "apellidos" => "Aparisi" ] 4 => array:2 [ "nombre" => "Dolors" "apellidos" => "Sánchez-Izquierdo" ] 5 => array:2 [ "nombre" => "Adela" "apellidos" => "Cañete" ] 6 => array:2 [ "nombre" => "José" "apellidos" => "Cervera" ] 7 => array:2 [ "nombre" => "José María" "apellidos" => "Millán" ] 8 => array:2 [ "nombre" => "Victoria" "apellidos" => "Castel" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2341287916301144" "doi" => "10.1016/j.anpede.2016.05.002" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2341287916301144?idApp=UINPBA00005H" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1695403316301990?idApp=UINPBA00005H" "url" => "/16954033/0000008500000005/v1_201610270011/S1695403316301990/v1_201610270011/es/main.assets" ] ] "itemSiguiente" => array:19 [ "pii" => "S2341287916301132" "issn" => "23412879" "doi" => "10.1016/j.anpede.2016.02.002" "estado" => "S300" "fechaPublicacion" => "2016-11-01" "aid" => "2065" "copyright" => "Asociación Española de Pediatría" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "An Pediatr (Barc). 2016;85:274.e1-8" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 1973 "formatos" => array:3 [ "EPUB" => 132 "HTML" => 1302 "PDF" => 539 ] ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Special Article</span>" "titulo" => "Liposomal cytarabine for the treatment of leptomeningeal dissemination of central nervous system tumours in children and adolescents" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "274.e1" "paginaFinal" => "274.e8" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Citarabina liposomal para el tratamiento de la diseminación leptomeníngea en tumores del sistema nervioso central en niños y adolescentes" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Lucas Moreno, Miguel Angel García Ariza, Ofelia Cruz, Carlota Calvo, José Luis Fuster, José Antonio Salinas, Cristina Moscardo, Raquel Portugal, José Manuel Merino, Luis Madero" "autores" => array:10 [ 0 => array:2 [ "nombre" => "Lucas" "apellidos" => "Moreno" ] 1 => array:2 [ "nombre" => "Miguel Angel" "apellidos" => "García Ariza" ] 2 => array:2 [ "nombre" => "Ofelia" "apellidos" => "Cruz" ] 3 => array:2 [ "nombre" => "Carlota" "apellidos" => "Calvo" ] 4 => array:2 [ "nombre" => "José Luis" "apellidos" => "Fuster" ] 5 => array:2 [ "nombre" => "José Antonio" "apellidos" => "Salinas" ] 6 => array:2 [ "nombre" => "Cristina" "apellidos" => "Moscardo" ] 7 => array:2 [ "nombre" => "Raquel" "apellidos" => "Portugal" ] 8 => array:2 [ "nombre" => "José Manuel" "apellidos" => "Merino" ] 9 => array:2 [ "nombre" => "Luis" "apellidos" => "Madero" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S1695403316000473" "doi" => "10.1016/j.anpedi.2016.02.007" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1695403316000473?idApp=UINPBA00005H" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2341287916301132?idApp=UINPBA00005H" "url" => "/23412879/0000008500000005/v1_201610270013/S2341287916301132/v1_201610270013/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S2341287916301090" "issn" => "23412879" "doi" => "10.1016/j.anpede.2016.09.001" "estado" => "S300" "fechaPublicacion" => "2016-11-01" "aid" => "2072" "copyright" => "Asociación Española de Pediatría" "documento" => "simple-article" "crossmark" => 1 "subdocumento" => "crp" "cita" => "An Pediatr (Barc). 2016;85:269-72" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 4890 "formatos" => array:3 [ "EPUB" => 169 "HTML" => 4022 "PDF" => 699 ] ] "en" => array:10 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Scientific Letter</span>" "titulo" => "Acute pancreatitis as a complication of <span class="elsevierStyleItalic">Salmonella</span> gastroenteritis, an unusual combination" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "269" "paginaFinal" => "272" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Pancreatitis aguda como complicación de gastroenteritis por <span class="elsevierStyleItalic">Salmonella</span>, una asociación poco habitual" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Jimena Pérez-Moreno, Lucía Carrascón González-Pinto, Felipe González Martínez, Blanca Toledo del Castillo, Rosa Rodríguez Fernández" "autores" => array:5 [ 0 => array:2 [ "nombre" => "Jimena" "apellidos" => "Pérez-Moreno" ] 1 => array:2 [ "nombre" => "Lucía" "apellidos" => "Carrascón González-Pinto" ] 2 => array:2 [ "nombre" => "Felipe" "apellidos" => "González Martínez" ] 3 => array:2 [ "nombre" => "Blanca" "apellidos" => "Toledo del Castillo" ] 4 => array:2 [ "nombre" => "Rosa" "apellidos" => "Rodríguez Fernández" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S1695403316300078" "doi" => "10.1016/j.anpedi.2016.02.011" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1695403316300078?idApp=UINPBA00005H" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2341287916301090?idApp=UINPBA00005H" "url" => "/23412879/0000008500000005/v1_201610270013/S2341287916301090/v1_201610270013/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Special Article</span>" "titulo" => "The new challenge in oncology: Next-generation sequencing and its application in precision medicine" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "273.e1" "paginaFinal" => "273.e7" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Inés Calabria, Laia Pedrola, Pablo Berlanga, María José Aparisi, Dolors Sánchez-Izquierdo, Adela Cañete, José Cervera, José María Millán, Victoria Castel" "autores" => array:9 [ 0 => array:3 [ "nombre" => "Inés" "apellidos" => "Calabria" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 1 => array:3 [ "nombre" => "Laia" "apellidos" => "Pedrola" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 2 => array:3 [ "nombre" => "Pablo" "apellidos" => "Berlanga" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 3 => array:3 [ "nombre" => "María José" "apellidos" => "Aparisi" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 4 => array:3 [ "nombre" => "Dolors" "apellidos" => "Sánchez-Izquierdo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 5 => array:3 [ "nombre" => "Adela" "apellidos" => "Cañete" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 6 => array:3 [ "nombre" => "José" "apellidos" => "Cervera" "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "aff0025" ] ] ] 7 => array:3 [ "nombre" => "José María" "apellidos" => "Millán" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] ] 8 => array:4 [ "nombre" => "Victoria" "apellidos" => "Castel" "email" => array:1 [ 0 => "castel_vic@gva.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:5 [ 0 => array:3 [ "entidad" => "Unidad de Oncología Pediátrica, Hospital Universitario y Politécnico La Fe, Valencia, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Investigación Clínica y Traslacional en Cáncer, Instituto de Investigación Sanitaria La Fe, Valencia, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Unidad Genómica, Instituto de Investigación Sanitaria La Fe, Valencia, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Unidad Genética, Hospital Universitario y Politécnico La Fe, Valencia, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Servicio de Hematología, Hospital Universitario y Politécnico La Fe, Valencia, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "El nuevo reto en oncología: la secuenciación NGS y su aplicación a la medicina de precisión" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The Human Genome Project, along with the development of high-throughput omic technologies such as next generation sequencing (NGS), has allowed rapid advances in our knowledge of disease-causing genetic alterations. The use of genetic data in clinical practice has led to a world-wide medical and scientific revolution, giving rise to a new model of health care delivery known as precision medicine or personalised medicine. There is abundant information on these emerging genomic technologies and their application to the diagnosis, prognosis and treatment of certain diseases. The aim of this review is to offer a clear and simple summary of the current situation of precision medicine in paediatric oncology, the most-recently developed sequencing technologies used in this field, and the suitability of this approach from the perspective of our experience in the Genomics and Paediatric Oncology units of the Instituto de Investigación Sanitaria and Hospital La Fe in Valencia.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">What is precision medicine?</span><p id="par0010" class="elsevierStylePara elsevierViewall">The concept of precision medicine is not new. In the past few decades, one of the pillars of oncology has been the application of tumour information at the gene, protein and environment levels in diagnosis and treatment.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">1</span></a> The process of integrating clinical, histological and molecular data for the purpose of choosing the optimal or most suitable treatment for the biological profile of the tumour is what constitutes precision medicine.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">2</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Traditionally, the molecular diagnosis of cancer based on the detection of single-nucleotide changes or small insertions or deletions in one or several genes was made by means of the Sanger sequencing method. Nowadays, due to the increasing number of genes that are known to be involved in cancer, the use of this technique is time-consuming and costly. Furthermore, it requires large amounts of tumour DNA, which may be difficult to obtain in some cases, and cannot detect DNA changes in subclonal populations. The development of NGS has revolutionised the approach to oncological diagnosis and provides more thorough and clinically applicable information on the molecular biology of tumours. Thanks to the development of these new technologies in combination with bioinformatic data analysis applications, the identification of pathogenic genomic alterations and of new genes associated with the development of specific diseases is now easier, faster and more cost-effective.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Genetics of childhood cancers</span><p id="par0020" class="elsevierStylePara elsevierViewall">The annual incidence of paediatric cancer in developed countries is 140–160 de novo cases per million children aged 0–14 years. Although the cure rate is higher than in adults, paediatric cancer is the leading cause of death by disease in children aged more than 1 year.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">3</span></a> In Spain, approximately 1000 cases of childhood cancer are diagnosed each year, an incidence that rises to 1500 for age up to 18 years.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">4</span></a> Despite significant increases in childhood cancer survival in recent decades, the prognosis of some tumour groups, such as high-grade glioma, brainstem tumours, medulloblastoma, and metastatic sarcomas and neuroblastomas, continues to be poor. Furthermore, survival is less than 20% in cases with metastatic relapse or progression, regardless of the used treatments.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">3</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Given the heterogeneous characteristics and genetic complexity of many tumours,<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">5</span></a> there is great variability in their response to treatment based on the altered molecular pathway. This is why an understanding of the molecular profile of the tumour is key to choose the most suitable treatment. In recent years, there have been significant advances in the molecular characterisation of different types of cancer that are invaluable tools for precision medicine.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">6</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">In addition to identify the genetic alterations that cause tumours, it is important to determine whether they are only found in the tumour (somatic mutation) or are constitutional in the patient and thus present in the blood (germline mutation). While only 5–10% of cancers are hereditary,<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">7</span></a> there are several types of germline cancer caused by known mutations. These cases are diagnosed differently and carry a different prognosis, and require genetic counselling since they not only increase the risk of carriers to develop cancer, but may also affect other members of the family and be passed on to the offspring. Recent studies have shown that approximately half of the patients with germline cancers do not have a relevant family history of cancer.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">8</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">A new biopsy for molecular analysis should be performed for every tumour relapse, as the pattern of genetic alterations may change from the one that was identified at the time of diagnosis. A study in patients with neuroblastoma showed that the mutation burden increases significantly in relapses compared to the time of diagnosis, so that molecular testing of relapsing tumours can be very useful to identify potential treatment targets on a case-to-case basis.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">9</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">At the molecular level, paediatric cancers differ from adult cancers in both the type and frequency of genetic defects.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">10</span></a> Most paediatric tumours form in growing tissues during early organ development.</p><p id="par0045" class="elsevierStylePara elsevierViewall">Several international initiatives have been launched with the purpose of elucidating cancer biology. The Cancer Genome Atlas is an ambitious project funded by the National Institute of Health of the United States whose objective is to make an exhaustive characterisation of each type of somatic cancer, in order to integrate all the information to establish the causes of the disease. The International Cancer Genome Consortium is an international project that is sequencing 50 tumour types. In the field of childhood cancer, various projects have been recently launched in the United States and Europe with the purpose of developing nationwide genetic screening programmes using commercially available gene panels for known mutations or whole exome and RNA sequencing (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">11–13</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Next generation sequencing</span><p id="par0050" class="elsevierStylePara elsevierViewall">In the past decade, we have progressed from sequencing a maximum of ninety-six 800 base pair sequences with first generation systems (Sanger method) to sequencing millions of DNA fragments with second generation systems (NGS). This novel technology is based on the amplification of DNA immobilised on a solid surface and the parallel reading of millions of sequences. The simultaneous sequencing of immobilised DNA reduces the amount of reactants needed as well as sequencing time, greatly reducing the cost per sequenced nucleotide. The vast amount of data generated by this technology poses a challenge to bioinformaticians, requiring the development of specific and user-friendly data analysis applications.</p><p id="par0055" class="elsevierStylePara elsevierViewall">In addition to the detection of point mutations, mass sequencing allows the detection of insertions, deletions, gene copy number changes and translocations. Another important aspect of the use of NGS in the study of cancer is the detection of somatic variants in tumour cell subpopulations that, as such, are present in low proportions in tumour samples. These subclonal mutations, which are undetectable by Sanger sequencing, are sometimes responsible for the recurrence or resistance to treatment of some tumours.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">18</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">We now proceed to describe the main NGS methods used in cancer diagnosis, along with their advantages and limitations:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">–</span><p id="par0065" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Gene panel sequencing:</span> panels contain primers or probes for a known group of genes and allow targeted sequencing for a specific disease. There are many commercially available panels, although they can also be made <span class="elsevierStyleItalic">a la carte</span>. They can be used to sequence known mutation regions (“hot spots”) and full genes, and allow the detection of gene copy number changes and translocations.</p><p id="par0070" class="elsevierStylePara elsevierViewall">Advantage: their design is optimised to sequence genes of interest with a high depth of coverage. This allows the detection of low-frequency variants and a quick and reliable analysis.</p><p id="par0075" class="elsevierStylePara elsevierViewall">Limitation: at present, commercial cancer panels are designed for testing in adults, and do not include regions that are relevant in childhood cancers. Furthermore, since they target known regions, they do not allow the detection of new genes potentially involved in cancer.</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">–</span><p id="par0080" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Whole exome sequencing</span> (WES): the exome is the part of the genome corresponding to the coding regions (exons) that can be expressed and lead to the production of proteins. It comprehends approximately 1.5% of the genome and is its most important functional part. From a technical standpoint, there are different possible approaches to sequencing the exome, such as the previous amplification of exons by polymerase chain reaction or their capture by specific probes.</p><p id="par0085" class="elsevierStylePara elsevierViewall">Advantage: allows the identification of genes and variants potentially involved in disease that have not yet been described.</p><p id="par0090" class="elsevierStylePara elsevierViewall">Limitations: due to the greater number of regions to be sequenced, it requires more readings than gene panel sequencing, and it is more feasible from an economic standpoint if a lower coverage depth is used, which precludes the detection of subclonal mutations. Furthermore, its analysis and interpretation are more complex due to the large number of variants that are detected (approximately 40,000), so in cancer patients it is recommended that paired-end sequencing of tumour samples and matched blood is performed to determine which of the variants are somatic.</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">–</span><p id="par0095" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Whole genome sequencing</span> (WGS): comprehends the entire genome of the individual, including chromosomal and mitochondrial DNA.</p><p id="par0100" class="elsevierStylePara elsevierViewall">Advantages: allows the identification of noncoding variants that may be associated to the disease. It is mainly used in research.</p><p id="par0105" class="elsevierStylePara elsevierViewall">Limitations: it has a high cost and the analysis is very complex, as noncoding regions of the genome are less conserved and present a higher number of variants. Furthermore, it requires high-throughput sequencing systems that are not available in the laboratories of most research facilities and hospitals in Spain. Consequently, it is less feasible for the purposes of diagnosis in everyday clinical practice.</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">–</span><p id="par0110" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Whole transcriptome sequencing</span> (WTS) or <span class="elsevierStyleItalic">RNA sequencing</span>: it can provide quantitative data on the genes expressed at a given time.</p><p id="par0115" class="elsevierStylePara elsevierViewall">Advantages: it allows the analysis of RNA transcripts, transcript isoforms, post-transcriptional modifications, gene fusion, mutations and changes in gene expression. It can be used to sequence different RNA populations (total RNA, small RNA, transfer RNA and ribosomal RNA).</p><p id="par0120" class="elsevierStylePara elsevierViewall">Limitations: the results obtained are tissue-specific and time-dependent, and may vary with sequencing depth. Their analysis and interpretation is very complex, and it is recommended that expression in healthy tissue be used for control.</p></li></ul></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Interpretation of genetic data obtained by next generation sequencing</span><p id="par0125" class="elsevierStylePara elsevierViewall">The correct interpretation of gene variants or detected mutations is key in precision medicine. Variants are detected by identifying differences in the DNA sequence of an individual compared to a reference sequence. However, the detection of variants in itself is not sufficient, as variants need to be interpreted by specialists to accurately determine their molecular and clinical implications and decide on the best treatment approach.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">19</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Databases of variants detected in the healthy population (polymorphisms) and of pathogenic variants are available for the interpretation of variants. In the case of unknown variants, bioinformatic applications are used to predict pathogenicity in silico. Various parameters are used to identify pathogenic variants and exclude polymorphisms:<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">–</span><p id="par0135" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Minor allele frequency</span> (MAF) <span class="elsevierStyleItalic">in the population</span>: frequency with which the least common allele appears in a specific population. A high MAF is associated with population polymorphisms.</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">–</span><p id="par0140" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Coverage:</span> number of times a nucleotide is sequenced. If the coverage of the variant is lower than expected based on tumour cellularity, it could be a technical artefact or a cell subclone with a different genomic profile. Artefacts tend to recur in different samples on the same sequencing lane and can be identified by means of a sequence viewer, such as IGV.</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">–</span><p id="par0145" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Variant location:</span> a variant may be exonic (which may lead to an amino acid change or be a synonymous mutation) or intronic (may or may not affect consensus splice sites leading to errors in protein coding).</p></li></ul></p><p id="par0150" class="elsevierStylePara elsevierViewall">In addition to these parameters, we would like to underscore the importance of recording every variant found in the sequencing of different samples with a single technique in an in-house laboratory database. This allows the easy detection of errors intrinsic to the technology (which recur in all samples) and frequent population polymorphisms, which facilitate the analysis and interpretation of data to a great extent.</p><p id="par0155" class="elsevierStylePara elsevierViewall">It is important to establish which category variants fit into: benign, likely benign, pathogenic, likely pathogenic or of uncertain clinical significance. A variant is benign when its MAF in the general population is greater than 2% or when it is categorised as such in the consulted databases (such as COSMIC [<a id="intr0010" class="elsevierStyleInterRef" href="http://cancer.sanger.ac.uk/cosmic">http://cancer.sanger.ac.uk/cosmic</a>] or ClinVar [<a id="intr0015" class="elsevierStyleInterRef" href="http://www.ncbi.nlm.nih.gov/clinvar/">http://www.ncbi.nlm.nih.gov/clinvar/</a>]). In the field of childhood cancer, there is the limitation that most variants are not described in existing databases, which calls for the use of in silico prediction tools that estimate the pathogenicity of mutations based on various aspects, such as allele frequencies in variant databases (1000G, <a id="intr0020" class="elsevierStyleInterRef" href="http://www.1000genomes.org/">http://www.1000genomes.org/</a>, ExAC <a id="intr0025" class="elsevierStyleInterRef" href="http://exac.broadinstitute.org/">http://exac.broadinstitute.org/</a>), protein structure (SIFT [<a id="intr0030" class="elsevierStyleInterRef" href="http://sift.jcvi.org/">http://sift.jcvi.org/</a>] and Polyphen2 [<a id="intr0035" class="elsevierStyleInterRef" href="http://genetics.bwh.harvard.edu/pph2/">http://genetics.bwh.harvard.edu/pph2/</a>]) or splicing site defects (NNSplice [<a id="intr0040" class="elsevierStyleInterRef" href="http://www.fruitfly.org/seq_tools/splice.html">http://www.fruitfly.org/seq_tools/splice.html</a>]; HSF [<a id="intr0045" class="elsevierStyleInterRef" href="http://www.umd.be/HSF/">http://www.umd.be/HSF/</a>], NetGene 2 [<a id="intr0050" class="elsevierStyleInterRef" href="http://www.cbs.dtu.dk/services/NetGene2/">http://www.cbs.dtu.dk/services/NetGene2/</a>] and SpliceView [<a id="intr0055" class="elsevierStyleInterRef" href="http://bioinfo4.itb.cnr.it/~webgene/wwwspliceview_ex.html]">http://bioinfo4.itb.cnr.it/∼webgene/wwwspliceview_ex.html]</a>). If the variant is not described in the consulted databases and several in silico prediction tools suggest that it is a benign mutation, it can be interpreted as a variant of uncertain clinical significance/likely benign. A variant is considered to be of uncertain clinical significance when it is not described in the consulted databases but could have an effect on gene function. The analysis of these variants involves the use of the aforementioned prediction tools and the estimation of a pathogenicity level by integrating other data contributed by pathologists, clinicians and bioinformaticians. A variant is considered pathogenic if different studies support its pathogenicity, and probably pathogenic when it is described as such in the literature or in the consulted databases, or when it has not been described but several prediction tools suggest that it is a pathogenic mutation.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Application of precision medicine to health care delivery. Opportunities for treatment</span><p id="par0160" class="elsevierStylePara elsevierViewall">In the past decade, most trials of molecularly targeted agents for the treatment of childhood cancers have been performed in unselected patients.<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">20</span></a> At present, few molecularly targeted therapies are available in the field of paediatric oncology. Those that are most widely used consist of drugs originally developed for other diseases in adults, such as ALK inhibitors, used in non-small cell lung carcinoma with <span class="elsevierStyleItalic">ALK</span> gene rearrangement, which have also proven effective in the treatment of anaplastic large-cell lymphoma and inflammatory myofibroblastic tumour (with <span class="elsevierStyleItalic">ALK</span> rearrangement) and neuroblastomas (with a mutation in <span class="elsevierStyleItalic">ALK</span>),<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">21</span></a> and BRAF inhibitors, used in melanoma, which are also effective in paediatric cases of <span class="elsevierStyleItalic">BRAF V600E</span>-mutated glioma.<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">22,23</span></a> The molecular analysis of <span class="elsevierStyleItalic">ALK</span> and <span class="elsevierStyleItalic">BRAF</span> in tumour tissue samples is part of the standard diagnostic protocol in most paediatric oncology clinics. However, the consecutive analysis of biomarkers is not compatible with clinical practice due to the limited availability of tumour material (which is usually obtained by a core needle biopsy at the time of diagnosis), the time required for each test, and the overall cost of the process.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">24</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">Our own experience, which is consistent with the data reported by other institutions in Spain and abroad, shows that it is possible to incorporate NGS to the clinical management of childhood cancer patients.<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">11–13</span></a> In November 2014, the Genomic Unit of the Instituto de Investigación Sanitaria La Fe (La Fe Public Health Research Institute) and the Paediatric Oncology Unit of the Hospital la Fe of Valencia established a close cooperation framework for the practice of precision medicine in paediatric patients with progressing or recurrent cancer.</p><p id="par0170" class="elsevierStylePara elsevierViewall">Most of the samples submitted to the Genomic Unit are analysed using NGS panels. The findings are discussed every fortnight by a precision medicine committee formed by pathologists, molecular biologists, geneticists and paediatric oncologists. This team discusses the pathogenicity of the detected variants, whether these variants open up new therapeutic options, and whether there are ongoing clinical trials that would fit specific patients. Achieving this rapid laboratory-to-clinic translation with real benefits for the patient is the greatest challenge of paediatric oncology at the moment.</p><p id="par0175" class="elsevierStylePara elsevierViewall">Applying the precision medicine protocol of our hospital, we evaluated 19 patients with progressing or recurrent solid tumours by means of NGS using a commercial hotspot mutation panel (CHSP v2; Thermofisher Scientific; Uppsala, Sweden). The median age at the time of inclusion in the study was 9.2 years (range, 3.6–16.4 years) and most patients had extracranial solid tumours (16), specifically neuroblastomas (7) and sarcomas (7).</p><p id="par0180" class="elsevierStylePara elsevierViewall">The analysed samples contained a minimum of 50% tumour cells. We found mutations that were potential therapeutic targets in eight of the nineteen patients. A mean of nineteen days elapsed between the time the biopsy or surgery was performed and the time that the molecular oncology committee made the corresponding recommendation.</p><p id="par0185" class="elsevierStylePara elsevierViewall">Three of the patients under study were treated with compassionate-use agents based on the genetic profile of their tumours. One of them received a diagnosis of Cowden syndrome based on genetic testing of a hamartomatous skin lesion that detected a de novo germline mutation (confirmed by testing of peripheral blood). This patient has been treated with everolimus and remained in partial remission after a year and a half of treatment. The second patient had a rapidly-progressing inflammatory myofibroblastic tumour that was resistant to ALK inhibitors and was treated with an mTOR inhibitor (temsirolimus) combined with irinotecan and temozolomide; the initial response was favourable, but the tumour started progressing after two months of treatment. The third patient had a neuroblastoma with a mutation in the <span class="elsevierStyleItalic">ALK</span> gene that progressed through several lines of treatment, and has recently enrolled in a phase I clinical trial for an ALK inhibitor.</p><p id="par0190" class="elsevierStylePara elsevierViewall">At present, thanks to the rapid development of high-throughput technologies and supporting bioinformatic programmes, we can analyse tumours at the molecular level to an unprecedented degree. We expect that this ability to study biological phenomena at the omic level will continue to lead to significant advances in precision medicine and in the identification of new, potentially treatable mutations and less frequent genetic alterations for which targeted therapies are already available, improving the prognosis of our patients.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conflict of interest</span><p id="par0195" class="elsevierStylePara elsevierViewall">The authors have no conflict of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres746748" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec749918" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres746749" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec749917" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "What is precision medicine?" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Genetics of childhood cancers" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Next generation sequencing" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Interpretation of genetic data obtained by next generation sequencing" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Application of precision medicine to health care delivery. Opportunities for treatment" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Conflict of interest" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-05-09" "fechaAceptado" => "2016-05-12" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec749918" "palabras" => array:3 [ 0 => "Precision medicine" 1 => "High throughput sequencing" 2 => "Cancer genetics" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec749917" "palabras" => array:3 [ 0 => "Medicina de precisión" 1 => "Secuenciación de alto rendimiento" 2 => "Genética del cáncer" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Precision medicine is an emerging approach for the diagnosis, treatment and prognosis of genetic diseases that enables clinicians to more accurately predict which treatment strategy will be optimal in a patient. The aim of Precision Medicine in Oncology is to integrate clinical, histological, and molecular data in order to obtain a deeper knowledge about the biology and genetics of an individual's tumour. Over the last few years, the implementation of new NGS (<span class="elsevierStyleItalic">Next Generation Sequencing</span>) technologies into clinical practice has been essential. There is a wide variety of NGS techniques that can be used in this context. The correct interpretation of molecular changes detected by these techniques is paramount for their appropriate use. In this review, a discussion is presented on the main NGS sequencing technologies that can be used to improve the diagnosis, prognosis, and treatment of oncology patients.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">El concepto de medicina de precisión ha cobrado especial relevancia en los últimos tiempos debido a la creciente necesidad de desarrollar estrategias personalizadas para el diagnóstico, el tratamiento y el seguimiento de diversas enfermedades de origen genético. La medicina de precisión en Oncología, a través de la integración de los datos clínicos, anatomopatológicos y moleculares, permite obtener un conocimiento más profundo del perfil biológico tumoral de cada paciente. En este contexto ha sido fundamental la implementación de las nuevas tecnologías de secuenciación <span class="elsevierStyleItalic">next generation sequencing</span> (NGS) en la práctica clínica. Existe un gran abanico de técnicas de secuenciación NGS que pueden ser utilizadas en función de la aplicación que se les quiera dar. La correcta interpretación de los cambios moleculares detectados mediante estas técnicas es clave para su adecuado uso en la práctica clínica. Esta revisión tiene como objetivo repasar las diferentes tecnologías de secuenciación que se utilizan actualmente en medicina de precisión para mejorar el diagnóstico, el pronóstico y el tratamiento de pacientes oncológicos.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0035">Please cite this article as: Calabria I, Pedrola L, Berlanga P, Aparisi MJ, Sánchez-Izquierdo D, Cañete A, et al. El nuevo reto en oncología: la secuenciación NGS y su aplicación a la medicina de precisión. An Pediatr (Barc). 2016;85:273.</p>" ] ] "multimedia" => array:1 [ 0 => 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" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">CGH, comparative genomic hybridisation; FISH, fluorescence in situ hybridisation; IHC, immunohistochemistry; WES, whole exome sequencing; WGS, whole genome sequencing.</p>" "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="left" valign="top" scope="col" style="border-bottom: 2px solid black">Study \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">Country \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">Inclusion criteria \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">Type of sample \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">Type of analysis \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">Sample size \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">Targetable mutations \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">BASIC<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">USA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">De novo solid tumours<br><18 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Frozen (initial diagnosis) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">WES \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">121 patients \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">22/80 \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">iCAT<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">USA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Refractory/recurrent high-risk extracranial solid tumours<br><30 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Paraffin (de novo or progressing/recurrent) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cancer panel (OncoMap<span class="elsevierStyleSup">®</span>/OncoPanel<span class="elsevierStyleSup">®</span>)<br>Array CGH<br>IHC, FISH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">89 patients \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">27/93 \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">Foundation Medicine Experience<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">USA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Solid tumours and leukaemias<br><21 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Paraffin (de novo or progressing/recurrent) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">FoundationOne<span class="elsevierStyleSup">®</span><br>FoundationOne Heme DNA<span class="elsevierStyleSup">®</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">400 samples \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">241/400 \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">MOSCATO-01<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">France \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Refractory/recurrent solid tumours<br><18 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Frozen \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ampliseq CHP2<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>custom<br>Array CGH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9 patients \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6/9 \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">INFORM<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">e</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Germany \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Refractory/recurrent high-risk leukaemias and solid tumours<br><40 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Frozen/paraffin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">WES<br>Low-coverage WGS<br>RNA Seq<br>Methylation arrays \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">48 patients \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">24/48 \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">Peds-MiOncoSeq<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">f</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">USA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Refractory/recurrent high-risk leukaemias and solid tumours<br><25 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Frozen/paraffin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">WES<br>RNA Seq \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">104 patients \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">43/104 \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">Hospital La Fe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Spain \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Progressing/recurrent solid tumours<br><18 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Frozen/paraffin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Panel (CHSP v2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">19 patients \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8/19 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1233458.png" ] ] ] "notaPie" => array:6 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Parsons et al.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">13</span></a></p>" ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Harris et al.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">12</span></a></p>" ] 2 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "c" "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Hawryluk et al.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">14</span></a></p>" ] 3 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "d" "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Georger et al.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">15</span></a></p>" ] 4 => array:3 [ "identificador" => "tblfn0025" "etiqueta" => "e" "nota" => "<p class="elsevierStyleNotepara" id="npar0025">German Cancer Research Center<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">16</span></a> and National Cancer Institute.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">17</span></a></p>" ] 5 => array:3 [ "identificador" => "tblfn0030" "etiqueta" => "f" "nota" => "<p class="elsevierStyleNotepara" id="npar0030">Mody et al.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">11</span></a></p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Nationwide tumour molecular screening projects in the United States and Europe.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:24 [ 0 => array:3 [ "identificador" => "bib0125" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available from: <a class="elsevierStyleInterRef" id="intr0060" href="http://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=561717">http://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=561717</a> [accessed 20.01.16]" "contribucion" => array:1 [ 0 => array:1 [ "titulo" => "NCI Dictionary of Cancer Terms" ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:1 [ "fecha" => "2016" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0130" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Multidisciplinary cancer care: does it improve outcomes?" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "S.S. Brar" 1 => "N.L. Hong" 2 => "F.C. Wright" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/jso.23700" "Revista" => array:7 [ "tituloSerie" => "J Surg Oncol" "fecha" => "2014" "volumen" => "110" "paginaInicial" => "494" "paginaFinal" => "499" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24986235" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0735109799006087" "estado" => "S300" "issn" => "07351097" ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0135" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Childhood cancer survival in Europe 1999–2007: results of EUROCARE 5 – a population-based study. EUROCARE Working Group" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G. Gatta" 1 => "L. Botta" 2 => "S. Rossi" 3 => "T. Aareleid" 4 => "M. Bielska-Lasota" 5 => "J. Clavel" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S1470-2045(13)70548-5" "Revista" => array:6 [ "tituloSerie" => "Lancet Oncol" "fecha" => "2014" "volumen" => "15" "paginaInicial" => "35" "paginaFinal" => "47" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24314616" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0140" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "(preliminary issue in CD-ROM) Available from: <a class="elsevierStyleInterRef" id="intr0065" href="http://www.uv.es/rnti">http://www.uv.es/rnti</a> [accessed 30.03.16]" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cáncer infantil en España. Estadísticas 1980–2014. Registro Nacional de Tumores Infantiles (RNTI-SEHOP)" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "R. Peris Bonet" 1 => "S. Felipe García" 2 => "N. Martínez Ruiz" 3 => "E. Pardo Romaguera" 4 => "S. Valero Poveda" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:3 [ "fecha" => "2014" "editorial" => "Universitat de València" "editorialLocalizacion" => "Valencia" ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0145" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cancer heterogeneity: implications for targeted therapeutics" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "R. Fisher" 1 => "L. Pusztai" 2 => "C. Swanton" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/bjc.2012.581" "Revista" => array:6 [ "tituloSerie" => "Br J Cancer" "fecha" => "2013" "volumen" => "108" "paginaInicial" => "479" "paginaFinal" => "485" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23299535" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0150" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Whole cancer genome sequencing by next-generation methods" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "J. Ross" 1 => "M. Cronin" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1309/AJCPR1SVT1VHUGXW" "Revista" => array:6 [ "tituloSerie" => "Am J Clin Pathol" "fecha" => "2011" "volumen" => "136" "paginaInicial" => "527" "paginaFinal" => "539" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21917674" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0155" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "10 rare tumors that warrant a genetics referral" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "K.C. Banks" 1 => "J.J. Moline" 2 => "M.L. Marvin" 3 => "A.C. Newlin" 4 => "K.J. Vogel" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s10689-012-9584-9" "Revista" => array:6 [ "tituloSerie" => "Fam Cancer" "fecha" => "2013" "volumen" => "12" "paginaInicial" => "1" "paginaFinal" => "18" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23377869" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0160" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "[Epub 2015 Nov 18]" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Germline mutations in predisposition genes in pediatric cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. Zhang" 1 => "M.F. Walsh" 2 => "G. Wu" 3 => "M.N. Edmonson" 4 => "T.A. Gruber" 5 => "J. Easton" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1508054" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2015" "volumen" => "373" "paginaInicial" => "2336" "paginaFinal" => "2346" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26580448" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0165" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mutational dynamics between primary and relapse neuroblastomas" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. Schramm" 1 => "J. Köster" 2 => "Y. Assenov" 3 => "K. Althoff" 4 => "M. Peifer" 5 => "E. Mahlow" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/ng.3349" "Revista" => array:6 [ "tituloSerie" => "Nat Genet" "fecha" => "2015" "volumen" => "47" "paginaInicial" => "872" "paginaFinal" => "877" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26121086" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0170" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Signatures of mutational processes in human cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "L.B. Alexandrov" 1 => "S. Nik-Zainal" 2 => "D.C. Wedge" 3 => "S.A. Aparicio" 4 => "S. Behjati" 5 => "A.V. Blankin" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/nature12477" "Revista" => array:6 [ "tituloSerie" => "Nature" "fecha" => "2013" "volumen" => "500" "paginaInicial" => "415" "paginaFinal" => "421" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23945592" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0175" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Integrative clinical sequencing in the management of refractory or relapsed cancer in youth" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R.J. Mody" 1 => "Y.M. Wu" 2 => "R.J. Lonigro" 3 => "X. Cao" 4 => "S. Roychowdhury" 5 => "P. Vats" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1001/jama.2015.10080" "Revista" => array:6 [ "tituloSerie" => "JAMA" "fecha" => "2015" "volumen" => "314" "paginaInicial" => "913" "paginaFinal" => "925" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26325560" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0180" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Multicenter feasibility study of tumor molecular profiling to inform therapeutic decisions in advanced pediatric solid tumors: The Individualized Cancer Therapy (iCat) Study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.H. Harris" 1 => "S.G. DuBois" 2 => "J.L. Glade Bender" 3 => "A. Kim" 4 => "B.D. Crompton" 5 => "E. Parker" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1001/jamaoncol.2015.5689" "Revista" => array:2 [ "tituloSerie" => "JAMA Oncol" "fecha" => "2016" ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0185" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diagnostic yield of clinical tumor and germline whole-exome sequencing for children with solid tumors" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D.W. Parsons" 1 => "A. Roy" 2 => "Y. Yang" 3 => "T. Wang" 4 => "S. Scollon" 5 => "K. Bergstrom" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1001/jamaoncol.2015.5699" "Revista" => array:2 [ "tituloSerie" => "JAMA Oncol" "fecha" => "2016" ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0190" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "[abstract 10035]" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical application of comprehensive next-generation sequencing-based genomic profiling for identification of actionable genomic alterations in pediatric solid tumours and hematolymphoid malignancies: The Foundation Medicine pediatric experience" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Hawryluk" 1 => "K. Wang" 2 => "J. Chmielecki" 3 => "S. Ali" 4 => "G. Palmer" 5 => "S. Downing" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2014" "volumen" => "32" "numero" => "Suppl" "paginaInicial" => "5s" ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0195" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "[abstract 10050]" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Molecular screening for cancer treatment optimization (MOSCATO 01) in pediatric patients: first feasibility results of a prospective molecular stratification trial" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "B. Georger" 1 => "F. Deschamps" 2 => "S. Puget" 3 => "V. Koubi-Pick" 4 => "L. Lacroix" 5 => "P. Vielh" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2013.49.0219" "Revista" => array:5 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2014" "numero" => "Suppl" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23897962" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0735109700007749" "estado" => "S300" "issn" => "07351097" ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0200" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available from: <a class="elsevierStyleInterRef" id="intr0070" href="https://www.dkfz.de/en/inform/protocol-synopsis.html">https://www.dkfz.de/en/inform/protocol-synopsis.html</a> [accessed 20.10.15]" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The Inform Registry. Individualized therapy for relapsed malignancies in childhood" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "German Cancer Research Center" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:1 [ "fecha" => "2015" ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0205" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available from: <a class="elsevierStyleInterRef" id="intr0075" href="http://www.cancer.gov/types/childhood-cancers/research/childhood-genomics-workshop-summary.pdf">http://www.cancer.gov/types/childhood-cancers/research/childhood-genomics-workshop-summary.pdf</a> [accessed 20.10.15]" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Childhood cancer genomics gaps and opportunities: identification of research priorities. Workshop Summary, February 4–5, 2015" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "National Cancer Institute" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:1 [ "fecha" => "2015" ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0210" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Emergence of new ALK mutations at relapse of neuroblastoma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G. Schleiermacher" 1 => "N. Javanmardi" 2 => "V. Bernard" 3 => "Q. Leroy" 4 => "J. Cappo" 5 => "T. Rio Frio" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2013.54.0674" "Revista" => array:6 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2014" "volumen" => "32" "paginaInicial" => "2727" "paginaFinal" => "2734" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25071110" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0215" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Guidelines for diagnostic next-generation sequencing" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G. Matthijs" 1 => "E. Souche" 2 => "M. Alders" 3 => "A. Corveleyn" 4 => "S. Eck" 5 => "I. Feenstra" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/ejhg.2015.226" "Revista" => array:6 [ "tituloSerie" => "Eur J Hum Genet" "fecha" => "2016" "volumen" => "24" "paginaInicial" => "2" "paginaFinal" => "5" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26508566" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0220" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Future of clinical genomics in pediatric oncology" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "K.A. Janeway" 1 => "A.E. Place" 2 => "M.W. Kieran" 3 => "M.H. Harris" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2012.46.8470" "Revista" => array:6 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2013" "volumen" => "31" "paginaInicial" => "1893" "paginaFinal" => "1903" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23589558" "web" => "Medline" ] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0225" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Biology-driven phase II trials: what is the optimal model for molecular selection?" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "F. Andre" 1 => "S. Decalogue" 2 => "J.C. Scoria" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2010.31.6877" "Revista" => array:6 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2011" "volumen" => "29" "paginaInicial" => "1236" "paginaFinal" => "1238" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21343554" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0230" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Complete clinical regression of a BRAF V600E-mutant pediatric glioblastoma multiforme after BRAF inhibitor therapy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "G.W. Robinson" 1 => "B.A. Orr" 2 => "A. Ajar" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/1471-2407-14-258" "Revista" => array:5 [ "tituloSerie" => "BMC Cancer" "fecha" => "2014" "volumen" => "14" "paginaInicial" => "258" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24725538" "web" => "Medline" ] ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0235" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children's Oncology Group phase 1 consortium study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Y.P. Mossé" 1 => "M.S. Lim" 2 => "S.D. Voss" 3 => "K. Wilmer" 4 => "K. Ruffner" 5 => "J. Laliberte" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S1470-2045(13)70095-0" "Revista" => array:6 [ "tituloSerie" => "Lancet Oncol" "fecha" => "2013" "volumen" => "14" "paginaInicial" => "472" "paginaFinal" => "480" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23598171" "web" => "Medline" ] ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0240" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Translating genomic discoveries to the clinic in pediatric oncology" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "J. Glade Bender" 1 => "A. Verma" 2 => "J.D. Schiffman" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/MOP.0000000000000172" "Revista" => array:6 [ "tituloSerie" => "Curr Opin Pediatr" "fecha" => "2015" "volumen" => "27" "paginaInicial" => "34" "paginaFinal" => "43" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25502895" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/23412879/0000008500000005/v1_201610270013/S2341287916301144/v1_201610270013/en/main.assets" "Apartado" => array:4 [ "identificador" => "44360" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Special Article" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/23412879/0000008500000005/v1_201610270013/S2341287916301144/v1_201610270013/en/main.pdf?idApp=UINPBA00005H&text.app=https://analesdepediatria.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2341287916301144?idApp=UINPBA00005H" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 13 | 10 | 23 |
| 2024 October | 63 | 57 | 120 |
| 2024 September | 91 | 51 | 142 |
| 2024 August | 84 | 55 | 139 |
| 2024 July | 63 | 33 | 96 |
| 2024 June | 115 | 31 | 146 |
| 2024 May | 71 | 38 | 109 |
| 2024 April | 52 | 40 | 92 |
| 2024 March | 55 | 33 | 88 |
| 2024 February | 36 | 22 | 58 |
| 2024 January | 50 | 30 | 80 |
| 2023 December | 33 | 24 | 57 |
| 2023 November | 43 | 25 | 68 |
| 2023 October | 29 | 40 | 69 |
| 2023 September | 37 | 25 | 62 |
| 2023 August | 42 | 20 | 62 |
| 2023 July | 42 | 22 | 64 |
| 2023 June | 36 | 28 | 64 |
| 2023 May | 50 | 25 | 75 |
| 2023 April | 27 | 19 | 46 |
| 2023 March | 57 | 24 | 81 |
| 2023 February | 56 | 21 | 77 |
| 2023 January | 27 | 25 | 52 |
| 2022 December | 50 | 28 | 78 |
| 2022 November | 66 | 33 | 99 |
| 2022 October | 60 | 39 | 99 |
| 2022 September | 31 | 42 | 73 |
| 2022 August | 41 | 64 | 105 |
| 2022 July | 41 | 40 | 81 |
| 2022 June | 37 | 41 | 78 |
| 2022 May | 36 | 36 | 72 |
| 2022 April | 54 | 52 | 106 |
| 2022 March | 44 | 46 | 90 |
| 2022 February | 32 | 28 | 60 |
| 2022 January | 47 | 41 | 88 |
| 2021 December | 56 | 35 | 91 |
| 2021 November | 56 | 43 | 99 |
| 2021 October | 69 | 71 | 140 |
| 2021 September | 31 | 46 | 77 |
| 2021 August | 28 | 48 | 76 |
| 2021 July | 18 | 34 | 52 |
| 2021 June | 36 | 50 | 86 |
| 2021 May | 44 | 42 | 86 |
| 2021 April | 91 | 83 | 174 |
| 2021 March | 50 | 33 | 83 |
| 2021 February | 37 | 39 | 76 |
| 2021 January | 53 | 43 | 96 |
| 2020 December | 27 | 25 | 52 |
| 2020 November | 24 | 28 | 52 |
| 2020 October | 26 | 21 | 47 |
| 2020 September | 26 | 21 | 47 |
| 2020 August | 23 | 25 | 48 |
| 2020 July | 29 | 21 | 50 |
| 2020 June | 22 | 19 | 41 |
| 2020 May | 40 | 30 | 70 |
| 2020 April | 25 | 23 | 48 |
| 2020 March | 24 | 26 | 50 |
| 2020 February | 46 | 24 | 70 |
| 2020 January | 25 | 20 | 45 |
| 2019 December | 48 | 26 | 74 |
| 2019 November | 33 | 22 | 55 |
| 2019 October | 29 | 24 | 53 |
| 2019 September | 23 | 10 | 33 |
| 2019 August | 71 | 24 | 95 |
| 2019 July | 47 | 37 | 84 |
| 2019 June | 40 | 19 | 59 |
| 2019 May | 123 | 60 | 183 |
| 2019 April | 73 | 25 | 98 |
| 2019 March | 37 | 18 | 55 |
| 2019 February | 36 | 15 | 51 |
| 2019 January | 35 | 34 | 69 |
| 2018 December | 41 | 24 | 65 |
| 2018 November | 122 | 32 | 154 |
| 2018 October | 109 | 49 | 158 |
| 2018 September | 32 | 30 | 62 |
| 2018 August | 4 | 0 | 4 |
| 2018 July | 2 | 0 | 2 |
| 2018 June | 5 | 0 | 5 |
| 2018 May | 9 | 0 | 9 |
| 2018 April | 35 | 0 | 35 |
| 2018 March | 46 | 0 | 46 |
| 2018 February | 18 | 0 | 18 |
| 2018 January | 20 | 0 | 20 |
| 2017 December | 22 | 0 | 22 |
| 2017 November | 18 | 0 | 18 |
| 2017 October | 16 | 0 | 16 |
| 2017 September | 22 | 0 | 22 |
| 2017 August | 17 | 0 | 17 |
| 2017 July | 23 | 1 | 24 |
| 2017 June | 23 | 10 | 33 |
| 2017 May | 33 | 16 | 49 |
| 2017 April | 22 | 20 | 42 |
| 2017 March | 17 | 20 | 37 |
| 2017 February | 14 | 10 | 24 |
| 2017 January | 11 | 20 | 31 |
| 2016 December | 29 | 30 | 59 |
| 2016 November | 56 | 67 | 123 |
| 2016 October | 17 | 24 | 41 |
Show all
