title: Age dependence of tumor genetics in unfavorable neuroblastoma: arrayCGH profiles of 34 consecutive cases, using a Swedish 25-year neuroblastoma cohort for validation.
abstract: BACKGROUND
  Aggressive neuroblastoma remains a significant cause of childhood cancer death despite current intensive multimodal treatment protocols. The purpose of the present work was to characterize the genetic and clinical diversity of such tumors by high resolution arrayCGH profiling.
  
  
  METHODS
  Based on a 32K BAC whole-genome tiling path array and using 50-250K Affymetrix SNP array platforms for verification, DNA copy number profiles were generated for 34 consecutive high-risk or lethal outcome neuroblastomas. In addition, age and MYCN amplification (MNA) status were retrieved for 112 unfavorable neuroblastomas of the Swedish Childhood Cancer Registry, representing a 25-year neuroblastoma cohort of Sweden, here used for validation of the findings. Statistical tests used were: Fisher's exact test, Bayes moderated t-test, independent samples t-test, and correlation analysis.
  
  
  RESULTS
  MNA or segmental 11q loss (11q-) was found in 28/34 tumors. With two exceptions, these aberrations were mutually exclusive. Children with MNA tumors were diagnosed at significantly younger ages than those with 11q- tumors (mean: 27.4 vs. 69.5 months; p=0.008; n=14/12), and MNA tumors had significantly fewer segmental chromosomal aberrations (mean: 5.5 vs. 12.0; p<0.001). Furthermore, in the 11q- tumor group a positive correlation was seen between the number of segmental aberrations and the age at diagnosis (Pearson Correlation 0.606; p=0.037). Among nonMNA/non11q- tumors (n=6), one tumor displayed amplicons on 11q and 12q and three others bore evidence of progression from low-risk tumors due to retrospective evidence of disease six years before diagnosis, or due to tumor profiles with high proportions of numerical chromosomal aberrations. An early age at diagnosis of MNA neuroblastomas was verified by registry data, with an average of 29.2 months for 43 cases that were not included in the present study.
  
  
  CONCLUSIONS
  MNA and segmental 11q loss define two major genetic variants of unfavorable neuroblastoma with apparent differences in their pace of tumor evolution and in genomic integrity. Other possible, but less common, routes in the development of aggressive tumors are progression of low-risk infant-type lesions, and gene amplifications other than MYCN. Knowledge on such nosological diversity of aggressive neuroblastoma might influence future strategies for therapy.
authors: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala SE-751 85, Sweden.
authors: Cihan
authors: C
authors: Cetinkaya
authors: Tommy
authors: T
authors: Martinsson
authors: Johanna
authors: J
authors: Sandgren
authors: Catarina
authors: C
authors: Träger
authors: Per
authors: P
authors: Kogner
authors: Jan
authors: J
authors: Dumanski
authors: Teresita
authors: T
authors: Díaz de Ståhl
authors: Fredrik
authors: F
authors: Hedborg
mesh_terms: D000293:Adolescent; D000367:Age Factors; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D056915:DNA Copy Number Variations; D005784:Gene Amplification; D020869:Gene Expression Profiling; D006801:Humans; D007223:Infant; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D015513:Oncogene Proteins / Q000235:genetics; D012042:Registries; D017384:Sequence Deletion; D013548:Sweden
chemical_list: C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins
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