Abstract
BackgroundAggressive 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.MethodsBased 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.ResultsMNA 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.ConclusionMNA 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.
Highlights
Aggressive neuroblastoma remains a significant cause of childhood cancer death despite current intensive multimodal treatment protocols
We examined the frequencies of copy number changes in tumor subgroups that were defined on the basis of the absence or presence of MYCN amplification (MNA) and segmental 11q loss (11q-); the tumors were separated into four subgroups: MNAnot11q(n=14), 11q-notMNA (n=12), MNA and 11q- (n=2), and neither MNA nor 11q- (n=6)
Analysis using Fisher’s exact test of differences between the MNAnot11qand 11q-notMNA groups revealed that loci on 1p, 2p, 3p, 5q, 7, 11, 12, 18p, and 20q were differentially altered between the two sets of tumors (Figure 1E)
Summary
Aggressive neuroblastoma remains a significant cause of childhood cancer death despite current intensive multimodal treatment protocols. Neuroblastoma is a childhood malignancy that arises from embryonic cells of the sympathetic ganglia or the adrenal medulla [1] It is mainly a disease of infants and toddlers; more than half of patients with neuroblastoma are diagnosed before two years of age and ~90 percent before age six [2,3]. The disease is clinically diverse, and ranges from cases with a very dismal prognosis, despite modern intensive multimodal therapy, to those with an excellent chance of survival [2]. This variation in clinical behavior is highly age dependent: children who are diagnosed after two years of age suffer predominantly from aggressive forms. Such tumors are usually less advanced, have a propensity for spontaneous involution or maturation, and respond well to mild chemotherapy [2]
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