FISH analyses for alterations in chromosomes 1, 2, 3, and 11 define high-risk groups in neuroblastoma.
BACKGROUND
The prognostic chromosomal markers 1p loss and MYCN amplification (MNA) are only present in a subgroup of approximately 30% of neuroblastomas. To further characterize high and low risk subsets we investigated alterations in chromosome arms 3p and 11q, additional changes in 1p and MYCN as well as the somy-status of chromosome 1 in the same sample.


METHODS
Fluorescence in situ hybridization (FISH) was used as an alternative technique to PCR/LOH- or comparative genomic hybridization (CGH) analyses. Alterations in chromosomes 3p and 11q were investigated in 182 unselected tumors, 1p loss and MNA in 174 and 179 of these, respectively. The somy-status of chromosome 1 was determined in 165 tumors as it highly correlates with the tumor ploidy.


RESULTS
Alterations in the four chromosomal regions were found in the following frequencies: 3p26: 19%, 11q23: 29%, 1p36: 29%, MNA: 19%. Fifty-two percent of all cases displayed structural aberrations in at least one chromosomal region, 83% in stage 4 and 30% in stages 1-3, 4s. All aberrations were thus correlated with stage 4 disease but were also present in a substantial subset of localized and 4s tumors. Trisomy of chromosome 1 was found in 38% of the tumors, disomy or tetrasomy in 62%. Patients with alterations in any of the four chromosomes and di/tetrasomy 1 showed a significantly increased age at diagnosis. Loss in 1p and MNA were closely associated with each other, as well as 3p and 11q aberrations but not the groups 1p/MNA versus 3p/11q. Only a small portion of trisomic tumors showed aberrations in at least one of the four chromosomal regions (14%) in contrast to the majority of the di/tetrasomic cases (74%). As already known the MYCN status discriminated between good and poor outcome in localized and metastatic stage 4 tumors. In addition alterations in 1p or 11q, deletion in 3p and di/tetrasomy 1 were associated with an unfavorable prognosis in MYCN single copy tumors of stages 1-3, 4s. Multivariate analysis revealed 11q alterations and MNA as the most important chromosomal prognostic factors in all stages.


CONCLUSIONS
FISH analyses for chromosomal alterations in 3p and 11q as well as in 1p and MYCN allows to define different groups with an increased risk for disease progression.
Spitz
Ruediger
R
University Children's Hospital, Pediatric Oncology, Köln, Germany. Ruedinger.Spitz@medizin.uni-koeln.de
Hero
Barbara
B
Ernestus
Karen
K
Berthold
Frank
F
D002648:Child; D002872:Chromosome Deletion; D002877:Chromosomes, Human / Q000235:genetics*; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D015331:Cohort Studies; D015342:DNA Probes; D005260:Female; D005858:Germany; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D000071447:N-Myc Proto-Oncogene Protein; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis; D009367:Neoplasm Staging; D009447:Neuroblastoma / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics*; D016016:Proportional Hazards Models; D016019:Survival Analysis
D015342:DNA Probes; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins