Editorial
Genetic predisposition to childhood cancer
Predisposición genética al cáncer infantil
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Los protooncogenes y los genes supresores de tumores tienen funciones antagónicas: los primeros promueven el crecimiento celular, mientras que los genes supresores de tumores codifican proteínas que inhiben la proliferación celular. Cuando se producen mutaciones esporádicas o heredadas en los protooncogenes se transforman en oncogenes, los cuales son capaces de orquestar la multiplicación anárquica de las células. En los genes supresores de tumores deben producirse 2 eventos mutacionales, según la teoría del segundo golpe de Knudson, para que se inicie el proceso tumoral. En el cáncer hereditario, la primera mutación es heredada y, por tanto, la probabilidad de presentar cáncer es mayor que en la población general.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Pilar Carrasco Salas, Pablo Lapunzina, Antonio Pérez-Martínez" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Pilar" "apellidos" => "Carrasco Salas" ] 1 => array:2 [ "nombre" => "Pablo" "apellidos" => "Lapunzina" ] 2 => array:2 [ "nombre" => "Antonio" "apellidos" => "Pérez-Martínez" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2341287917301369" "doi" => "10.1016/j.anpede.2017.01.003" "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/S2341287917301369?idApp=UINPBA00005H" ] ] "EPUB" => 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0 => array:2 [ "autoresLista" => "César García Vera, María García Ventura, Guadalupe del Castillo Aguas, Begoña Domínguez Aurrecoechea, María Jesús Esparza Olcina, Ana Martínez Rubio, José María Mengual Gil" "autores" => array:8 [ 0 => array:2 [ "nombre" => "César" "apellidos" => "García Vera" ] 1 => array:2 [ "nombre" => "María" "apellidos" => "García Ventura" ] 2 => array:2 [ "nombre" => "Guadalupe" "apellidos" => "del Castillo Aguas" ] 3 => array:2 [ "nombre" => "Begoña" "apellidos" => "Domínguez Aurrecoechea" ] 4 => array:2 [ "nombre" => "María Jesús" "apellidos" => "Esparza Olcina" ] 5 => array:2 [ "nombre" => "Ana" "apellidos" => "Martínez Rubio" ] 6 => array:2 [ "nombre" => "José María" "apellidos" => "Mengual Gil" ] 7 => array:1 [ "colaborador" => "Red de Vigilancia Epidemiológica de Pediatría de Atención Primaria (PAPenRED)" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S1695403316301904" "doi" => "10.1016/j.anpedi.2016.04.020" 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"apellidos" => "Carrasco Salas" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "Pablo" "apellidos" => "Lapunzina" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:4 [ "nombre" => "Antonio" "apellidos" => "Pérez-Martínez" "email" => array:1 [ 0 => "aperezmartinez@salud.madrid.org" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Laboratorio de Oncohematología Pediátrica Molecular, Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Hemato-Oncología Pediátrica, Hospital Infantil Universitario La Paz, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Predisposición genética al cáncer infantil" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1742 "Ancho" => 2269 "Tamanyo" => 278311 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Role of tumour-suppressor genes and proto-oncogenes in tumour development. Proto-oncogenes and tumour-suppressor genes function as antagonists: the former promote cell growth, while the latter inhibit cell proliferation. When sporadic or inherited mutations occur in proto-oncogenes, they become oncogenes that can orchestrate uncontrolled cell proliferation. According to Knudson's two-hit hypothesis, two mutation events need to take place in tumour-suppressor genes for tumour development to start. In hereditary cancer, the first mutation is inherited and thus the probability of having cancer is greater than that of the general population.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">In developing countries, childhood cancer is the leading cause of death due to illness in the paediatric age group. Its incidence has been growing continuously since the 1950s<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">1</span></a> due to advances in diagnostic tools and cancer registers, which has been associated with considerable improvements in prognosis and survival.</p><p id="par0010" class="elsevierStylePara elsevierViewall">However, the cure of childhood cancer seems to have met a therapeutic ceiling, plateauing at 70% in the past few decades.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">2</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">We currently know that childhood cancer is a disease of multifactorial aetiology whose genetic basis is not entirely understood, with considerable involvement of the immune system and modulated by exposure to environmental factors.</p><p id="par0020" class="elsevierStylePara elsevierViewall">At present, preventive measures are ineffective against childhood cancer. However, the detection of hereditary susceptibility could be very relevant to patients and families. In some cases, it could lead to the implementation of preventive measures for the early detection of malignancies, both in the index case and in blood relatives.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">The genetics of cancer</span><p id="par0030" class="elsevierStylePara elsevierViewall">Cancer results from the accumulation of different genetic changes in a cell, sometimes over several years. These changes lead to abnormal cell proliferation and clonal expansion, which can ultimately invade other tissues.</p><p id="par0035" class="elsevierStylePara elsevierViewall">In most cases, genetic changes that promote tumorigenesis occur in somatic cells and do not involve germline mutations.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Numerous genes involved in tumour development have been identified, and are classified into 3 different categories: tumour-suppressor genes, proto-oncogenes and genes involved in genome stability. Tumour-suppressor genes control cell proliferation, inhibiting the progression of the cell cycle or inducing apoptosis (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Usually, a single functional copy of the gene suffices to carry out its function. The inactivation of both alleles allows uncontrolled proliferation and thus contributes to tumour development. Conversely, proto-oncogenes promote cell proliferation and contribute to tumour progression when they are permanently activated as a result of mutations. In this case, mutations in a single allele suffice to produce uncontrolled proliferation. Genes involved in DNA stability do not play a direct role in the regulation of cell proliferation, but dysfunction in these genes contributes to an increased number of mutations and thus to an increased probability of tumour development.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">3</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Hereditary predisposition to cancer</span><p id="par0045" class="elsevierStylePara elsevierViewall">Broadly speaking, a hereditary susceptibility to cancer is suspected in families with 2 or more relatives in the same side of the family with the same type of cancer, several affected generations, earlier ages of diagnosis, individuals with multiple primary cancers, occurrence of different types of cancer that are genetically related (such as breast and ovarian cancer, or colon and uterine cancer), increased frequency of bilateral or multifocal as opposed to unilateral involvement, occurrence of nonmalignant and malignant changes in the same individual or family (for instance, Marfanoid habitus and multiple endocrine neoplasias type 2B). However, because of phenotypic variability and age differences in penetrance, many families may not fulfil these criteria.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">4</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Most of the genes involved in the genetic predisposition to cancer are tumour-suppressor genes, and gain-of-function mutations in proto-oncogenes are only found in 10% of cases. In cases of predisposition due to mutations in tumour-suppressor genes, individuals inherit a defective copy of the gene, but based on Knudson's two-hit hypothesis, tumour development requires the somatic loss of the other allele. For this reason, mutations in tumour-suppressor genes are considered recessive. Since the probability of a mutation occurring in a single gene is higher than the probability of it occurring in the 2 alleles of the gene, the incidence of cancer in carriers of germline mutations of tumour-suppressor genes is much higher than that of the general population.</p><p id="par0055" class="elsevierStylePara elsevierViewall">The case of carriers of dominant or gain-of-function mutations in proto-oncogenes is different. Although a mutation in a single allele suffices for cancer to occur, the presence of such a mutation does not necessarily result in the individual developing cancer. This will depend on the clinical penetrance of each type of tumour.</p><p id="par0060" class="elsevierStylePara elsevierViewall">Genetic predisposition to cancer is due to mutations present in every cell of the body. These mutations, known as germline mutations because they were acquired <span class="elsevierStyleItalic">via</span> the germ cells, are prezygotic and may have been inherited or result from a <span class="elsevierStyleItalic">de novo</span> mutation in the germ cells of one of the progenitors (ova or spermatozoa). In the latter case, it would be the first time the mutation occurred in the family. In an individual without a genetic predisposition to cancer, mutations occur in somatic cells and are postzygotic.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Clinical implications of genetic predisposition to childhood cancer</span><p id="par0065" class="elsevierStylePara elsevierViewall">The application of novel gene sequencing techniques in children with cancer is allowing us to expand our understanding of the molecular basis of childhood tumours. Unlike conventional molecular techniques, high-throughput techniques such as massive sequencing or next generation sequencing (NGS) can sequence millions of DNA fragments in parallel with progressively decreasing costs and shorter times. They can also detect different types of genomic changes with a single test.</p><p id="par0070" class="elsevierStylePara elsevierViewall">A recent study included whole-genome sequencing by NGS of 1120 cancer patients aged 0 to 19 years. It found that 8.5% had germline mutations that predisposed to cancer, compared to 1% of the control group.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">5</span></a> The fact that there is a significantly higher percentage of germline mutations that predispose to cancer in the population of cancer patients raises several questions: would it be ethical and cost-effective to perform routine genetic screening of neonates with the purpose of identifying patients at risk of developing cancer? Would it be feasible to follow up all of these patients? Would they be able to benefit from an early diagnosis?</p><p id="par0075" class="elsevierStylePara elsevierViewall">On the other hand, this same study found similar cancer histories in the families of patients with cancer and controls, which may be due to the young age of the parents, to the changes being <span class="elsevierStyleItalic">de novo</span> mutations (segregation analyses were not performed) or to incomplete documentation of the family history. This finding suggests that, on one hand, a positive family history should not be the sole indication for performing genetic testing in families, and on the other, that in some families, index cases may occur in the paediatric age group in the absence of adult cancers.</p><p id="par0080" class="elsevierStylePara elsevierViewall">It would be interesting to conduct further studies to determine whether there is a high prevalence of inherited predisposing mutations. This would let us know whether detection of such mutations in probands would not only be useful to these individuals but also to their relatives. Genetic testing of relatives of cancer patients could identify other at-risk individuals that may benefit from early intervention, improving the associated morbidity and mortality.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "The genetics of cancer" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "Hereditary predisposition to cancer" ] 3 => array:2 [ "identificador" => "sec0020" "titulo" => "Clinical implications of genetic predisposition to childhood cancer" ] 4 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Carrasco Salas P, Lapunzina P, Pérez-Martínez A. Predisposición genética al cáncer infantil. An Pediatr (Barc). 2017;87:125–127.</p>" ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1742 "Ancho" => 2269 "Tamanyo" => 278311 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Role of tumour-suppressor genes and proto-oncogenes in tumour development. Proto-oncogenes and tumour-suppressor genes function as antagonists: the former promote cell growth, while the latter inhibit cell proliferation. When sporadic or inherited mutations occur in proto-oncogenes, they become oncogenes that can orchestrate uncontrolled cell proliferation. According to Knudson's two-hit hypothesis, two mutation events need to take place in tumour-suppressor genes for tumour development to start. In hereditary cancer, the first mutation is inherited and thus the probability of having cancer is greater than that of the general population.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:5 [ 0 => array:3 [ "identificador" => "bib0030" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Childhood cancer incidence and survival in Spain" "autores" => array:1 [ 0 => array:3 [ "colaboracion" => "Spanish Childhood Cancer Epidemiology Working Group" "etal" => true "autores" => array:6 [ 0 => "R. Peris-Bonet" 1 => "D. Salmerón" 2 => "M.A. Martínez-Beneito" 3 => "J. Galceran" 4 => "R. Marcos-Gragera" 5 => "S. 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Eng" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/sj.onc.1207714" "Revista" => array:6 [ "tituloSerie" => "Oncogene" "fecha" => "2004" "volumen" => "23" "paginaInicial" => "6445" "paginaFinal" => "6470" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15322516" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0050" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "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" ] ] ] ] ] ] ] ] ] ] ] ] "agradecimientos" => array:1 [ 0 => array:3 [ "titulo" => "Acknowledgements" "texto" => "<p id="par0085" class="elsevierStylePara elsevierViewall">We want to thank the <span class="elsevierStyleGrantSponsor" id="gs1">Fundación Cris contra el Cáncer</span> (<span class="elsevierStyleInterRef" id="intr0010" href="http://www.criscancer.org/es">http://www.criscancer.org/es</span>) and the <span class="elsevierStyleGrantSponsor" id="gs2">Fundación Uno Entre Cien Mil</span> (<span class="elsevierStyleInterRef" id="intr0015" href="http://unoentrecienmil.org/">http://unoentrecienmil.org/</span>) for their support in this project.</p>" "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/23412879/0000008700000003/v2_201708291341/S2341287917301369/v2_201708291341/en/main.assets" "Apartado" => array:4 [ "identificador" => "25501" "tipo" => "SECCION" "es" => array:2 [ "titulo" => "Editorial" "idiomaDefecto" => true ] "idiomaDefecto" => "es" ] "PDF" => "https://static.elsevier.es/multimedia/23412879/0000008700000003/v2_201708291341/S2341287917301369/v2_201708291341/en/main.pdf?idApp=UINPBA00005H&text.app=https://analesdepediatria.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2341287917301369?idApp=UINPBA00005H" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 4 | 10 | 14 |
| 2024 October | 59 | 44 | 103 |
| 2024 September | 68 | 36 | 104 |
| 2024 August | 76 | 61 | 137 |
| 2024 July | 96 | 29 | 125 |
| 2024 June | 102 | 35 | 137 |
| 2024 May | 84 | 43 | 127 |
| 2024 April | 74 | 38 | 112 |
| 2024 March | 64 | 24 | 88 |
| 2024 February | 61 | 36 | 97 |
| 2024 January | 63 | 19 | 82 |
| 2023 December | 111 | 28 | 139 |
| 2023 November | 69 | 30 | 99 |
| 2023 October | 64 | 25 | 89 |
| 2023 September | 46 | 22 | 68 |
| 2023 August | 56 | 12 | 68 |
| 2023 July | 75 | 37 | 112 |
| 2023 June | 58 | 23 | 81 |
| 2023 May | 84 | 24 | 108 |
| 2023 April | 44 | 17 | 61 |
| 2023 March | 77 | 60 | 137 |
| 2023 February | 55 | 12 | 67 |
| 2023 January | 53 | 34 | 87 |
| 2022 December | 64 | 33 | 97 |
| 2022 November | 56 | 22 | 78 |
| 2022 October | 80 | 48 | 128 |
| 2022 September | 75 | 37 | 112 |
| 2022 August | 59 | 55 | 114 |
| 2022 July | 54 | 36 | 90 |
| 2022 June | 73 | 45 | 118 |
| 2022 May | 78 | 56 | 134 |
| 2022 April | 69 | 39 | 108 |
| 2022 March | 94 | 66 | 160 |
| 2022 February | 68 | 28 | 96 |
| 2022 January | 61 | 39 | 100 |
| 2021 December | 64 | 47 | 111 |
| 2021 November | 72 | 56 | 128 |
| 2021 October | 131 | 87 | 218 |
| 2021 September | 79 | 49 | 128 |
| 2021 August | 44 | 47 | 91 |
| 2021 July | 63 | 30 | 93 |
| 2021 June | 50 | 69 | 119 |
| 2021 May | 80 | 44 | 124 |
| 2021 April | 164 | 68 | 232 |
| 2021 March | 87 | 52 | 139 |
| 2021 February | 78 | 24 | 102 |
| 2021 January | 95 | 37 | 132 |
| 2020 December | 71 | 26 | 97 |
| 2020 November | 99 | 31 | 130 |
| 2020 October | 214 | 26 | 240 |
| 2020 September | 189 | 35 | 224 |
| 2020 August | 107 | 18 | 125 |
| 2020 July | 121 | 27 | 148 |
| 2020 June | 115 | 21 | 136 |
| 2020 May | 89 | 27 | 116 |
| 2020 April | 57 | 23 | 80 |
| 2020 March | 48 | 27 | 75 |
| 2020 February | 53 | 14 | 67 |
| 2020 January | 61 | 18 | 79 |
| 2019 December | 60 | 22 | 82 |
| 2019 November | 38 | 19 | 57 |
| 2019 October | 43 | 16 | 59 |
| 2019 September | 43 | 13 | 56 |
| 2019 August | 46 | 26 | 72 |
| 2019 July | 38 | 19 | 57 |
| 2019 June | 44 | 18 | 62 |
| 2019 May | 78 | 10 | 88 |
| 2019 April | 82 | 23 | 105 |
| 2019 March | 23 | 14 | 37 |
| 2019 February | 36 | 11 | 47 |
| 2019 January | 34 | 20 | 54 |
| 2018 December | 25 | 23 | 48 |
| 2018 November | 56 | 25 | 81 |
| 2018 October | 40 | 23 | 63 |
| 2018 September | 32 | 16 | 48 |
| 2018 August | 1 | 0 | 1 |
| 2018 July | 7 | 0 | 7 |
| 2018 June | 5 | 0 | 5 |
| 2018 May | 9 | 0 | 9 |
| 2018 April | 25 | 0 | 25 |
| 2018 March | 37 | 0 | 37 |
| 2018 February | 12 | 0 | 12 |
| 2018 January | 23 | 0 | 23 |
| 2017 December | 31 | 0 | 31 |
| 2017 November | 38 | 0 | 38 |
| 2017 October | 23 | 0 | 23 |
| 2017 August | 0 | 13 | 13 |
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