High-risk neuroblastoma tumors with 11q-deletion display a poor prognostic, chromosome instability phenotype with later onset

Abstract

Analysis of chromosomal aberrations is used to determine the prognosis of neuroblastomas (NBs) and to aid treatment decisions. MYCN amplification (MNA) alone is an incomplete poor prognostic factor, and chromosome 11q status has recently been included in risk classification. We analyzed 165 NB tumors using high-density SNP microarrays and specifically compared the high-risk groups defined by MNA (n = 37) and 11q-deletion (n = 21). Median patient age at diagnosis was 21 months for MNA tumors and 42 months for 11q-deletion tumors, and median survival time after diagnosis was 16 months for MNA and 40 months for 11q deletion. Overall survival (at 8 years) was approximately 35% in both groups. MNA and 11q deletion were almost mutually exclusive; only one case harbored both aberrations. The numbers of segmental aberrations differed significantly; the MNA group had a median of four aberrations, whereas the 11q-deletion group had 12. The high frequency of chromosomal breaks in the 11q-deletion group is suggestive of a chromosomal instability phenotype gene located in 11q; one such gene, H2AFX, is located in 11q23.3 (within the 11q-deletion region). Furthermore, in the groups with segmental aberrations without MNA or 11q deletion, the tumors with 17q gain have worse prognosis than those with segmental aberrations without 17q gain, which have a favorable outcome. This study has implications for therapy in different risk groups and stresses that genome-wide microarray analyses should be included in clinical management to fully evaluate risk, aid diagnosis, and guide treatment.

Fig. 1.

Summary of SNP array data of gains and losses for 134 NB cases. Horizontal lines show segmental loss (clear blue) and gain (clear red) and whole chromosome loss (pale blue) and gain (pale red). Short vertical lines show amplification (brown) or homozygous loss (dark blue). The genomic profile group is indicated to the left. The inclusion features for the three high-risk groups—MYCN amplification, 11q deletion, and 17q gain—are indicated by dotted ovals. Note that only one case has both MYCN amplification and 11q deletion. Patients who have died of disease are indicated to the right by filled black circles, whereas patients who are still alive and have an overall survival of at least 5 years are indicated by open circles. Two cases in the numerical-only group are represented by a horizontal line; these patients died of surgical complications. Cases with a flat profile (n = 31) are not shown. See Materials and Methods for definitions of the genomic groups.

Fig. 2.

Boxplots showing that the 11q-deletion tumors have significantly more chromosomal breaks than the other groups. (A) Number of chromosomes with chromosomal breaks for each case. (B) Number of chromosomal breaks per case. In the boxplots, the upper and lower hinges of the box represent the 75th and 25th percentiles, respectively; whiskers indicate the highest and lowest values that are not outliers or extreme values; the thick horizontal line represents the median; open circles represent outliers; and asterisks represent extremes. The groups were compared after adjustment for ascertainment biases. The level of significance for the difference between the 11q-deleted and MYCN-amplified groups is indicated in both figures.

Fig. 3.

Age at diagnosis of the 165 NB patients by genomic profile group, showing a significant difference in age at diagnosis between groups of MYCN-amplified cases versus 11q-deleted cases. (A) Boxplot showing age at diagnosis by group. (B) Cumulative age at diagnosis of disease.

Fig. 4.

Kaplan-Meier overall survival for patients with tumors with different genomic profiles. The tumors are grouped as follows: the other segmental group (red line), the numerical-only group (blue line), the 17q-gain group (violet line), the MYCN-amplification group (yellow line), and the 11q-deletion group (green line). The single case with both MYCN amplification and 11q deletion was omitted from the analysis. See Materials and Methods for definitions of the genomic profile groups.