Analysis of neuroblastoma tumour progression;: loss of PHOX2B on 4p13 and 17q gain are early events in neuroblastoma tumourigenesis

被引:1
作者
Krona, Cecilia [1 ]
Caren, Helena [1 ]
Sjoberg, Rose-Marie [1 ]
Sandstedt, Bengt [2 ]
Laureys, Genevieve [3 ]
Kogner, Per [2 ]
Martinsson, Tommy [1 ]
机构
[1] Univ Gothenburg, Inst Biomed, Dept Clin Genet, SE-41345 Gothenburg, Sweden
[2] Karolinska Inst, Dept Woman & Child Hlth, Childhood Canc Res Unit, SE-17176 Stockholm, Sweden
[3] Ghent Univ Hosp, Dept Pediat Hematooncol, B-9000 Ghent, Belgium
关键词
PHOX2B; neuroblastoma; tumour progression; multifocal-tumour; neural crest cell;
D O I
暂无
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Neuroblastomas are biologically and clinically heterogeneous tumours that most often occur sporadically in children at median age of 2 years. The PHOX2B gene is implicated in the development of the autonomic nervous system and has been found to be infrequently mutated in sporadic neuroblastoma tumours and in some patients with hereditary neuroblastoma. We have screened a selected series of 36 paediatric tumours with presumed genetic predisposition, 34 of them neuroblastomas, for mutations in PHOX2B. A constitutional heterozygous missense mutation was found in a boy who developed bilateral adrenal tumours and stage 4 disease during infancy. The second allele of the PHOX2B locus was lost in the tumour DNA. Histopathological evaluation of the tumours suggested growth of two primary tumours, one with diploid DNA content and the other with tetraploid DNA content, i.e. a case of neuroblastoma stage 4, (multifocal tumour). However, array CGH (comparative genomic hybridization) data performed on both tumour masses from the patient instead supported a model where a common malignant precursor gave rise to the diploid tumour and subsequently the tetraploid tumour have progressed from the common precursor or by metastasis from the diploid tumour with additional genetic changes. The whole genome dosage analysis showed that the remaining alleles of PHOX2B had been lost in both tumours together with a specific 17q gain pattern. The tetraploid tumour had these features together with additional whole chromosomal loss of chromosomes 3, 9, 14 and 15. Based on the data presented here we suggest that loss of PHOX2B and 17q gain are early events in neuroblastoma tumourigenesis. We also propose investigators to re-analyze the rare cases of multifocal neuroblastomas with the array CGH technique for better understanding of the origin of these tumours.
引用
收藏
页码:575 / 583
页数:9
相关论文
共 36 条
[1]   Gain of chromosome arm 17q is associated with unfavourable prognosis in neuroblastoma, but does not involve mutations in the somatostatin receptor 2 (SSTR2) gene at 17q24 [J].
Abel, F ;
Ejeskär, K ;
Kogner, P ;
Martinsson, T .
BRITISH JOURNAL OF CANCER, 1999, 81 (08) :1402-1409
[2]   Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome [J].
Amiel, J ;
Laudier, B ;
Attié-Bitach, T ;
Trang, H ;
de Pontual, L ;
Gener, B ;
Trochet, D ;
Etchevers, H ;
Ray, P ;
Simonneau, M ;
Vekemans, M ;
Munnich, A ;
Gaultier, C ;
Lyonnet, S .
NATURE GENETICS, 2003, 33 (04) :459-461
[3]   Gain of chromosome arm 17q and adverse outcome in patients with neuroblastoma [J].
Bown, N ;
Cotterill, S ;
Lastowska, M ;
O'Neill, S ;
Pearson, ADJ ;
Plantaz, D ;
Meddeb, M ;
Danglot, G ;
Brinkschmidt, C ;
Christiansen, H ;
Laureys, G ;
Speleman, F .
NEW ENGLAND JOURNAL OF MEDICINE, 1999, 340 (25) :1954-1961
[4]   REVISIONS OF THE INTERNATIONAL CRITERIA FOR NEUROBLASTOMA DIAGNOSIS, STAGING, AND RESPONSE TO TREATMENT [J].
BRODEUR, GM ;
PRITCHARD, J ;
BERTHOLD, F ;
CARLSEN, NLT ;
CASTEL, V ;
CASTLEBERRY, RP ;
DEBERNARDI, B ;
EVANS, AE ;
FAVROT, M ;
HEDBORG, F ;
KANEKO, M ;
KEMSHEAD, J ;
LAMPERT, F ;
LEE, REJ ;
LOOK, AT ;
PEARSON, ADJ ;
PHILIP, T ;
ROALD, B ;
SAWADA, T ;
SEEGER, RC ;
TSUCHIDA, Y ;
VOUTE, PA .
JOURNAL OF CLINICAL ONCOLOGY, 1993, 11 (08) :1466-1477
[5]  
BRODEUR GM, 1981, CANCER RES, V41, P4678
[6]   INTERNATIONAL CRITERIA FOR DIAGNOSIS, STAGING, AND RESPONSE TO TREATMENT IN PATIENTS WITH NEURO-BLASTOMA [J].
BRODEUR, GM ;
SEEGER, RC ;
BARRETT, A ;
BERTHOLD, F ;
CASTLEBERRY, RP ;
DANGIO, G ;
DEBERNARDI, B ;
EVANS, AE ;
FAVROT, M ;
FREEMAN, AI ;
HAASE, G ;
HARTMANN, O ;
HAYES, FA ;
HELSON, L ;
KEMSHEAD, J ;
LAMPERT, F ;
NINANE, J ;
OHKAWA, H ;
PHILIP, T ;
PINKERTON, CR ;
PRITCHARD, J ;
SAWADA, T ;
SIEGEL, S ;
SMITH, EI ;
TSUCHIDA, Y ;
VOUTE, PA .
JOURNAL OF CLINICAL ONCOLOGY, 1988, 6 (12) :1874-1881
[7]   Phox2 genes -: from patterning to connectivity [J].
Brunet, JF ;
Pattyn, A .
CURRENT OPINION IN GENETICS & DEVELOPMENT, 2002, 12 (04) :435-440
[8]  
Dubreuil W, 2002, DEVELOPMENT, V129, P5241
[9]  
Fröstad B, 1999, CANCER CYTOPATHOL, V87, P60
[10]   ABNORMALITIES OF CHROMOSOME 1P IN HUMAN NEURO-BLASTOMA TUMORS AND CELL-LINES [J].
GILBERT, F ;
BALABAN, G ;
MOORHEAD, P ;
BIANCHI, D ;
SCHLESINGER, H .
CANCER GENETICS AND CYTOGENETICS, 1982, 7 (01) :33-42