Información del artículo
Los estudios de genética molecular en el cáncer infantil han ido adquiriendo en los últimos años una importancia trascendental. Los avances en estas técnicas han permitido aumentar el conocimiento de distintos genes implicados en el desarrollo tumoral. Estas diferentes alteraciones génicas ocurren en tres grandes grupos de genes: oncogenes, genes supresores y genes reparadores de ADN. Los estudios citogenéticos (cariotipo) se complementan con diferentes técnicas moleculares como la hibridación in situ con fluorescencia (FISH), la transcripción inversa acoplada a la reacción en cadena de la polimerasa (RT-pCR) o el cariotipo espectral (SKY), como más fiables, mejorando su sensibilidad
En este artículo se repasan los genes más representativos y mejor estudiados implicados en la etiología molecular del cáncer pediátrico, tanto de neoplasias hematológicas (leucemias y linfomas) como de tumores sólidos (tumores cerebrales, neuroblastoma, tumor de Wilms, hepatoblastoma, rabdomiosarcoma, sarcoma de Ewing y retinoblastoma), y cómo su estudio, además de permitir alcanzar un diagnóstico más preciso, ha desarrollado nuevos factores pronóstico y tratamientos más efectivos. Estas técnicas también pueden utilizarse en busca de la enfermedad mínima residual, durante y tras finalizar el tratamiento en leucemias, neuroblastomas y sarcomas, con el fin de prevenir su reaparición
Palabras clave:
Citogenética
Genética molecular
RT-pCR
FISH
Alteraciones cromosómicas
Neoplasias hematológicas
Tumores sólidos
Enfermedad mínima residual
In the last few years molecular genetic studies of childhood cancer have acquired great importance. Advances in these techniques have increased knowledge of the various genes involved in tumoral development. Genetic alterations can occur in three large groups of genes: oncogenes, tumor suppressor genes, and DNA repair genes. Cytogenetic analyses (karyotyping) are complemented by various molecular techniques, such as fluorescence in situ hybridization (FISH), reverse transcriptase-polymerase chain reaction (RT-pCR) and spectral karyotyping (SKY). These are the most reliable techniques and improve the sensitivity of karyotyping
The present article reviews the most representative and best characterized genes involved in the molecular etiology of childhood cancer, both hematologic malignancies (leukemia and lymphoma) and solid tumors (brain tumors, neuroblastoma, Wilms' tumor, hepatoblastoma, rhabdomyosarcoma, Ewing's sarcoma and retinoblastoma). Molecular techniques have enabled more precise diagnosis as well as identification of new prognostic factors and the development of more effective treatments. These techniques can also be useful in identifying minimal residual disease during and after treatment for leukemias, neuroblastomas and sarcomas, with the aim of predicting recurrence
Key words:
Cytogenetics
Molecular genetics
RT-pCR
FISH
Chromosomal abnormalities
Hematologic malignancies
Solid tumors
Minimal residual disease
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Bibliografía
[1.]
A. Muñoz.
Introducción a la oncología pediátrica.
Hematología y oncología pediátricas, 1.a ed, pp. 197-206
[2.]
J.L. Young, L.G. Ries, E. Silverberg, J.W. Horm, R.W. Miller.
Cancer incidence, survival and mortality for children younger than age 15 years.
Cancer, 58 (1986), pp. 598-602
[3.]
A.T. Look, I.R. Kirsch.
Molecular basis of childhood cancer.
Principles and practice of pediatric oncology, 4th ed, pp. 45-87
[4.]
J.A. Martínez, V. Castel, J. García-Conde.
Citogenética molecular del cáncer infantil: aplicaciones clínicas.
Med Clin (Barc), 111 (1998), pp. 389-397
[5.]
J.E. Rubnitz, W.M. Crist.
Molecular genetics of childhood cancer: Implications for pathogenesis, diagnosis, and treatment.
Pediatrics, 100 (1997), pp. 101-108
[6.]
L. Castaño, J.R. Bilbao, B. Calvo.
Introducción a la biología molecular y aplicación a la pediatría (3): Enzimas de restricción. Reacción en cadena de la polimerasa. Forma de estudio de mutaciones.
An Esp Pediatr, 46 (1997), pp. 87-92
[7.]
C.J. Harrison.
The management of patients with leukemia: The role of cytogenetics in this molecular area.
Br J Haematol, 108 (2000), pp. 19-30
[8.]
W.M. Crist, A.J. Carroll, J. Shuster, J. Jackson, D. Head, M. Borowitz, et al.
Philadelphia chromosome positive childhood acute lymphoblastic leukaemia: Clinical and cytogenetic characteristics and treatment outcome. A Pediatric Oncology Group Study.
Blood, 76 (1990), pp. 489-494
[9.]
E. Forestier, B. Johansson, G. Gustafsson, G. Borgstom, G. Kerndrup, J. Johannsson, et al.
Prognostic impact of karyotypic findings in childhood acute lymphoblastic leukemia: For the Nordic Society of Paediatric Haematology and Oncology (NOPHO) Leukemia Cytogenetic Study Group.
Br J Haematol, 110 (2000), pp. 147-153
[10.]
A. Biondi, G. Cimino, R. Pieters, C.H. Pui.
Biological and therapeutical aspects of infant leukemia.
Blood, 96 (2000), pp. 24-33
[11.]
E. Coustan-Smith, J. Sancho, M.L. Hancock, J.M. Boyett, F.G. Behm, S.C. Raimondi, et al.
Clinical importance of minimal residual disease in childhood acute leukemia.
Blood, 96 (2000), pp. 2691-2696
[12.]
P. Bolufer, E. Barragan, A. Verdeguer, J. cervera, J.M. Fernández, I. Moreno, et al.
Rapid quantitative detection of TEL-AML1 fusion transcripts in pediatric acute lymphoblastic leukaemia by real-time reverse transcription polymerase chain reaction using fluorescently labelled probes.
Haematologica, 87 (2002), pp. 23-32
[13.]
C.H. Pui, D. Campana.
New definition of remission in childhood acute lymphoblastic leukaemia.
Leukemia, 14 (2000), pp. 783-785
[14.]
C. Eckert, A. Biondi, K. Seeger, G. Cazzaniga, R. Hartmann, B. Beyermann, et al.
Prognostic value of minimal residual disease in relapsed childhood acute lymphoblastic leukaemia.
Lancet, 358 (2001), pp. 1239-1241
[15.]
J.A. Martínez-Climent, N. Lane, C.M. Rubin, E. Morgan, H.S. Johnstone, R. Mick, et al.
Clinical and prognostic significance of chromosomal abnormalities in childhood acute myeloid leukemia.
Leukemia, 9 (1995), pp. 95-101
[16.]
Z. Xiao, M.F. Greaves, P. Buffler, M.T. Smith, M.R. Segal, B.M. Dicks, et al.
Molecular characterization of genomic AML1-ETO fusions in childhood leukaemia.
Leukemia, 15 (2001), pp. 1906-1913
[17.]
D. Diverio, V. Rossi, G. Avvisati, S. De Santis, A. Pistilli, F. Pane, et al.
Early detection of relapse by prospective RT-pCR analysis of the PML-RAR afusion gene in patients with acute promyelocytic leukaemia enrolled in the GIMEMA-AIEOP multicenter "AIDA" trial.
Blood, 92 (1998), pp. 784-789
[18.]
P. Fernaux, C. Chastang, S. Cheveret, M. Sanz, H. Dombret, E. Archimbaud, et al.
A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group.
Blood, 94 (1999), pp. 1192-1200
[19.]
J.T. Sandlund, J.R. Downing, W.M. Crist.
Non-Hodgkin's lymphoma in childhood.
N Engl J Med, 334 (1996), pp. 1238-1248
[20.]
C.G. Sherman, M. Zielenska, A.N. Lorenzana, K.A. Pulford, D.Y. Mason, R.E. Hutchinson, et al.
Morphological and phenotypic features in pediatric large cell lymphoma and their correlation with ALK expression and the t(2;5)(p23;q35) traslocation.
Pediatr Dev Pathol, 4 (2001), pp. 129-137
[21.]
R.B. Lorsbach, D. Shay-Seymore, J. Moore, P.M. Banks, R.P. Hasserjian, J.T. Sandlund, et al.
Clinicopathologic analysis of follicular lymphoma occurring in children.
Blood, 99 (2002), pp. 1959-1964
[22.]
B.H. Kushner, M.P. LaQuaglia, N.K. Cheung, K. Kramer, A.C. Hamelin, W.L. Gerald, et al.
Clinically critical impact of molecular genetic studies in pediatric solid tumors.
Med Pediatr Oncol, 33 (1999), pp. 530-535
[23.]
A.M. Davidoff, D.A. Hill.
Molecular genetic aspects of solid tumors in childhood.
Semin Pediatr Surg, 10 (2001), pp. 106-118
[24.]
D.R. Strother, I.F. Pollack, P.G. Fisher, J.V. Hunter, S.Y. Woo, S.L. Pomeroy, et al.
Tumors of the central nervous system.
Principles and practice of Pediatric Oncology, 4th ed, pp. 751-824
[26.]
I.A. Pollack, S.D. Finkelstein, J. Woods, J. Burnham, E.J. Holmes, R.L. Hamilton, et al.
Expression of p53 and prognosis in children with malignant gliomas.
N Engl J Med, 346 (2002), pp. 420-427
[27.]
E.M. Michiels, M.M. Weiss, J.M. Hoovers, J.P. Baak, P.A. Voute, F. Bass, et al.
Genetic alterations in childhood medulloblastoma analysed by comparative genomic hybridization.
J Pediatr Hematol Oncol, 24 (2002), pp. 205-210
[28.]
S.L. Pomeroy, P. Tamayo, M. Gaasenbeek, L.M. Sturla, M. Angelo, M.E. McLaughlin, et al.
Prediction of nervous system embryonal tumour outcome based on gene expression.
Nature, 415 (2002), pp. 436-442
[29.]
J.A. López Andreu, J. Ferrís Tortajada, A. Verdeguer Miralles, C. Font de Mora Lleó, C. Esquembre Menor, V. Castel Sánchez.
Factores pronósticos del neuroblastoma.
An Esp Pediatr, 41 (1994), pp. 309-314
[30.]
T. Tajiri, K. Shono, S. Tanaka, S. Suita.
Evaluation of genetic heterogeneity in neuroblastoma.
Surgery, 131 (2002), pp. 283-287
[31.]
H. Caron, P. Van Sluis, J. De Kraker, J. Bokkerink, M. Egeler, S.G. Laurey, et al.
Allelic loss of chromosome 1p as a predictor of unfavorable outcome in patients with neuroblastoma.
N Engl J Med, 334 (1996), pp. 225-230
[32.]
P.S. White, P.M. Thompson, B.A. Seifried, E.P. Sulman, S.J. Jensen, C. Guo, et al.
Detailed molecular analysis of 1p36 in neuroblastoma.
Med Pediatr Oncol, 36 (2001), pp. 37-41
[33.]
C.M. McConville, S. Dyer, S.A. Rees, M.E. Luttikhuis, D.J. McMullan, S.J. Vickers, et al.
Molecular cytogenetic charecterization of two non-MYCN amplified neuroblastoma cell lines with complex t(11;17).
Cancer Genet Cytogenet, 130 (2001), pp. 133-140
[34.]
B. Stark, M. Jeison, I. Bar-Am, L. Glaser-Gabay, J. Mardoukh, D. Luria, et al.
Distinct cytogenetic pathways of advanced-stage neuroblastoma tumors, detected by spectral karyotyping.
Genes Chromosomes Cancer, 34 (2002), pp. 313-324
[35.]
I.Y. Cheung, N.K. Cheung.
Detection of microscopic disease: Comparing histology, inmunocytology, and RT-pCR of tyrosine hydroxylase, GAGE, and MAGE.
Med Pediatr Oncol, 36 (2001), pp. 210-212
[36.]
S.A. Burchill, S.E. Kinsey, S. Picton, P. Roberts, C.R. Pinkerton, P. Selby, et al.
Minimal residual disease at the time of peripheral blood stem cell harvest in patients with advanced neuroblastoma.
Med Pediatr Oncol, 36 (2001), pp. 213-219
[37.]
A. Pagani, L. Macri, L.B. Faulkner, V. Tintori, A. Paoli, A. Garaventa, et al.
Detection procedures for neuroblastoma cells metastatic to blood and bone marrow: Blinded comparison of chromagranin A heminested reverse transcription polymerase chain reaction to tyrosine hydroxylase nested reverse transcription polymerase chain reaction and to anti-GD2 immunocytology.
Diagn Mol Pathol, 11 (2002), pp. 98-106
[39.]
R. Barnoud, O. Delattre, M. Peoc'h, D. Pasquier, D. Plantaz, D. Leroux, et al.
Desmoplastic small round cell tumor: RT-pCR análisis and immunohistochemical detection of the Wilm's tumor gene WT1.
Pathol Res Pract, 194 (1998), pp. 693-700
[40.]
M. Gessler, A. Konig, J. Moore, S. Qualman, K. Arden, W. Kavenee, et al.
Homozygous inactivation of WT1 in Wilm's tumor associated with the WAGR syndrome.
Genes Chromosomes Cancer, 7 (1993), pp. 131-136
[41.]
C. Vicanek, E. Ferretti, C. Goodyer, E. Torban, P. Moffett, J. Pelletier, et al.
Regulation of renal EGF receptor expression in normal in Denys-Drash syndrome.
Kidney Int, 52 (1997), pp. 614-619
[42.]
M.J. Coppes, D.A. Haber, P.E. Grundy.
Genetic events in the development of Wilm's tumor.
N Engl J Med, 331 (1994), pp. 586-590
[43.]
K. Malik, P. Yan, T.H.M. Huang, K.W. Brown.
Wilm's tumor: A paradigm for the new genetics.
Oncol Res, 12 (2001), pp. 441-449
[44.]
D. Von Schweinitz, J.A. Kraus, S. Albrecht, A. Kock, J. Fuchs, Pietsch.
Prognostic impact of molecular genetic alterations in hepatoblastoma.
Med Pediatr Oncol, 38 (2002), pp. 104-108
[45.]
y. Udatsu, T. Kusafuca, S. Kuroda, J. Miao, A. Okada.
High frequency of beta-catenin mutations in hepatoblastoma.
Pediatr Surg Int, 17 (2001), pp. 508-512
[46.]
S.J. Xia, J.G. Pressey, F.G. Barr.
Molecular pathogenesis of rhabdomyosarcoma.
Cancer Biol Ther, 1 (2002), pp. 97-104
[47.]
L. De Zen, A. Sommaggio, E.S. d'Amore, L. Masiero, L.C. di Montezemolo, A. Linari, et al.
Clinical relevance of DNA ploidy and proliferative activity in childhood rhabdomyosarcoma: A retrospective análisis of patines enrrolled into the Italian Cooperative Rhabdomyosarcoma Study RMS88.
J Clin Oncol, 15 (1997), pp. 1198-1205
[48.]
T. Gordon, A. McManus, J. Anderson, T. Min, J. Swasbury, K. Pritchard- Jones, et al.
Cytogenetic abnormalities in 42 rhabdomyosarcoma: A United Kingdom cancer Cytogenetics Group Study.
Med Pediatr Oncol, 36 (2001), pp. 259-267
[49.]
P.H. Sorensen, J.C. Lynch, S.J. Qualman, R. Tirabosco, J.F. Lim, H.M. Maurer, et al.
PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: A report from the children's oncology group.
J Clin Oncol, 20 (2002), pp. 2672-2679
[50.]
E. De Álava, J. Pardo.
Ewing tumor: Tumor biology and clinical applications.
Int J Surg Pathol, 9 (2001), pp. 7-17
[51.]
S. Gururangan, N.M. Marina, X. Luo, D.M. Partham, C.Y. Tzen, C.A. Greenwald, et al.
Treatment of children with peripheral primitive neuroectodermal or extraosseous Ewing's tumor with Ewing's-directed therapy.
J Pediatr Hematol Oncol, 20 (1998), pp. 55-61
[52.]
H.E. Grier, M.D. Krailo, N.J. Tarbell, M.P. Link, C.J. Fryer, D.J. Prichard, et al.
Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone.
N Engl J Med, 348 (2003), pp. 694-701
[53.]
R. Dagher, T.A. Pham, L. Sorbara, S. Kumar, L. Long, D. Bernstein, et al.
Molecular confirmation of Ewing sarcoma.
J Pediatr Hematol Oncol, 23 (2001), pp. 221-224
[54.]
E. De Alava, A. Kawai, J.H. Healey, I. Fligman, P.A. Meyers, A.G. Huvos, et al.
EWS-FLI1 fusion transcript structure is an independent determinant of prognosis in Ewing's sarcoma.
J Clin Oncol, 16 (1998), pp. 1248-1255
[55.]
G. Amir, J. Issakov, I. Meller, E. Sucher, A. Peyser, I.J. Cohen, et al.
Expression of p53 gene product and cell proliferation marker ki-67 in Ewing's sarcoma: Correlation with clinical outcome.
Hum Pathol, 33 (2002), pp. 170-174
[56.]
L. Sierrasesúmaga, A. Patiño.
Retinoblastoma.
Hematología y Oncología pediátricas, 1.a ed, pp. 573-582
[57.]
J.r. Knudson AG.
Mutation and cancer: Statistical study of retinoblastoma.
Proc Natl Acad Sci USA, 68 (1971), pp. 820-823
[58.]
A. Stahl, N. Levy, T. Wadzynska, J.M. Sussan, D. Jourdan-Fonta, J.B. Saracco.
The genetics of retinoblastoma.
Ann Genet, 37 (1994), pp. 172-178
[59.]
L. Zheng, W.H. Lee.
The retinoblastoma gene: A prototypic and multifunctional tumor suppressor.
Exp cell Res, 264 (2001), pp. 2-18
[60.]
J. Alonso, P. García-Miguel, J. Abelairas, M. Mendiola, A. Pestana.
A microsatellite fluorescent meted for linkage análisis in familial retinoblastoma and deletion delection at the RB1 locus in retinoblastoma and osteosarcoma.
Diagn Mol Pathol, 10 (2001), pp. 9-14
[61.]
J. Alonso, P. García-Miguel, J. Abelairas, M. Mendiola, E. Sarret, M.T. Vendrell, et al.
Spectrum of germline RB1 gene mutations in spanish retinoblastoma patients: Phenotypic and molecular epidemiological implications.
Hum Mutat, 17 (2001), pp. 412-422
[62.]
T.J. Triche, D. Schofield, J. Buckley.
DNA microarrays in pediatric cancer.
Cancer J, 7 (2001), pp. 2-15
[63.]
S. Ramaswamy, T.R. Golub.
DNA microarrays in clinical oncology.
J Clin Oncol, 20 (2002), pp. 1932-1941
[64.]
T.J. Yeatman.
The future of clinical cancer management: One tumor, one chip.
Am Surg, 69 (2003), pp. 41-44
[65.]
A. Rojas-Martínez, I.A. Martínez-Dávila, A. Hernández-García, E. Aguilar-Córdova, H.A. Barrera-Saldaña.
Terapia génica del cáncer.
Rev Invest Clin, 54 (2002), pp. 57-67
[66.]
R.Y. Chung, E.A. Chiocca.
Gene therapy for tumors of the central nervous system.
Surg Oncol Clin North Am, 7 (1998), pp. 589-602
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