Analysis of candidate gene co-amplification with MYCN in neuroblastoma.
Previous studies have revealed that the MYCN gene spans approximately 7kb, while the amplicon has been estimated to be 100 kb to 1 Mb long [1-3]. This implies that several other genes may be present on the MYCN amplicon. Such co-amplified genes could contribute to the malignant phenotype and might provide an explanation for why not all patients with MYCN amplification have a poor outcome. We investigated 7 neuroblastoma cell lines and 167 primary tumours for the co-amplification of candidate genes known to be present near the MYCN locus: ornithine decarboxylase, ribonucleotide reductase, syndecan-1 and a DEAD box protein gene, DDX1. We also investigated further the pG21 expressed sequence previously reported to be co-amplified with MYCN. No co-amplification with the first 3 genes was found in any of the cell lines or tumour samples. DDX1 was found to be amplified along with MYCN in 4/6 (67%) cell lines and 18/38 (47%) of the MYCN amplified tumours. No amplification of DDX1, ODC1, RRM2 or syndecan-1 was found in the absence of MYCN amplification. DDX1 co-amplification was observed to occur mainly in stage 4 or 4S patients. With the exclusion of those with 4S disease, patients with DDX1 co-amplification had a significantly shorter mean (+/- SE) disease-free interval (4.1 +/- 1.4, n = 8 months) compared with patients with MYCN amplification alone (19.6 +/- 4.5, n = 17) (P = 0.04, Welch's unpaired t-test). The pG21 sequence was identical to part of the DDX1 gene. These observations indicate that there is at least 1 other gene co-amplified with MYCN in a proportion of cases and that those patients with DDX1 co-amplification tend to relapse more quickly. It also implies that the MYCN amplicon is of varied size and/or position relative to the MYCN gene.
George
R E
RE
Cancer Research Unit, Newcastle University Medical School, University of Newcastle upon Tyne, U.K.
Kenyon
R
R
McGuckin
A G
AG
Kohl
N
N
Kogner
P
P
Christiansen
H
H
Pearson
A D
AD
Lunec
J
J
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005784:Gene Amplification; D005796:Genes / Q000235:genetics*; D016259:Genes, myc / Q000235:genetics*; D006801:Humans; D007223:Infant; D009367:Neoplasm Staging; D009447:Neuroblastoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D014407:Tumor Cells, Cultured