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Clinical Cancer Research Vol. 12, 3368-3373, June 1, 2006
© 2006 American Association for Cancer Research

Imaging, Diagnosis, Prognosis

Loss in Chromosome 11q Identifies Tumors with Increased Risk for Metastatic Relapses in Localized and 4S Neuroblastoma

Ruediger Spitz1,2, Barbara Hero1,2, Thorsten Simon1,2 and Frank Berthold1,2

Authors' Affiliations: 1 Department of Pediatric Oncology, University Children's Hospital, Köln, Germany and 2 Center for Molecular Medicine Cologne, Cologne, Germany

Requests for reprints: Ruediger Spitz, Department of Pediatric Oncology and Hematology, University Children's Hospital, Kerpener-Str. 62, 50924 Köln, Germany. Phone: 49-221-478-6816; Fax: 49-221-478-4689; E-mail: Ruediger.Spitz{at}uk-koeln.de.


   Abstract
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 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Purpose: To improve risk prediction in neuroblastoma and to specify the type of a possible relapse, alterations in the long arm of chromosome 11 were analyzed.

Experimental Design: A representative cohort of 611 neuroblastomas was investigated for deletion events in distal chromosome 11q using interphase fluorescence in situ hybridization.

Results: Alterations in 11q were found in 159 of 611 tumors in the whole cohort (26%) and were associated with stage 4 disease (P < 0.001) and age at diagnosis of >2.5 years (P < 0.001). Event-free survival and overall survival were significantly poorer for patients with 11q loss in the whole cohort (event-free survival and overall survival, P < 0.001) and in different subsets: neuroblastoma without MYCN amplification (MNA) (event-free survival and overall survival, P < 0.001), with MNA (event-free survival, P = 0.03; overall survival, P = 0.02), and MYCN-nonamplified stage 1, 2, 3, and 4S tumors with and without del 1p (event-free survival and overall survival, P < 0.001). In stage 4, the 11q status did not discriminate outcome. By multivariate analysis, the 11q status proved prognostic for event-free survival in the whole cohort (P = 0.008; hazard ratio, 1.573) and in the subgroup of stages 1, 2, 3, and 4S without MNA (P < 0.001; hazard ratio, 3.534). Moreover, 11q alterations were strongly correlated with the occurrence of metastatic relapses (P < 0.001).

Conclusion: In addition to the current risk stratification, the status of 11q enables the identification of patients with an increased risk for relapses in general and metastatic relapses in particular.

Intensive investigation of molecular alterations in neuroblastomas during recent years has produced a promising although still insufficient risk estimation at present. Unsolved problems are the identification of patients from the estimated good-risk group who develop tumor progressions during their course of the disease and the identification of good-risk children within the poor-risk group.

One molecular marker with high specificity is the amplified MYCN oncogene (1, 2), predicting unfavorable outcome reliably in tumors of all stages and ages. Because of the low prevalence of MYCN amplification (~20%; refs. 3, 4), further molecular markers are essential for a comprehensive risk stratification. Deletion events in distal 1p are seen in ~30% of all tumors and show a close correlation with MYCN amplification and with poor outcome (5, 6). A substantial number of tumors with increased risk, however, remain undetected. Rearrangement resulting in loss of material in 11q with a prevalence similar to 1p deletions (7, 8) defines a different subgroup of neuroblastomas (9), mostly nonamplified high-risk tumors and often associated with loss in 3p (8, 10). Several studies disclosed an association between 11q alterations and unfavorable course (7, 8, 11, 12), although results were not always consistent (13). Due to small patient cohorts with limited numbers of heterogeneous events and difficulties in technical evaluation, the practical use of the 11q status remained elusive. The aim of this study was a precise definition of the prognostic effect of 11q loss in neuroblastomas. Using the fluorescence in situ hybridization technique, we investigated the large number of 611 tumors representing 224 events to achieve sufficient statistical power even in several clinical or biological subgroups. The present study provides the most detailed and comprehensive description of the influence of 11q deletions on the quantity and for the first time on the quality of relapses.


   Materials and Methods
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Tumor tissue samples of 611 unselected neuroblastoma patients were analyzed: 528 (86%) before any treatment and 83 (14%) after cytotoxic treatment. A subset of these tumors (n = 144) was used in a previous analysis (8).

According to the International Staging System, tumors were classified as stage 1 (n = 140, 23%), stage 2 (n = 98, 16%), stage 3 (n = 96, 16%), stage 4 (n = 215, 35%), and stage 4S (n = 62, 10%). Tissue specimens were obtained as tumor touch preparations (78%), frozen or paraffin-embedded sliced cut sections (10%), or bone marrow aspirates (12%). To ensure a tumor content of at least 50%, each slide was checked by a pathologist.

Patients were registered and treated in the German Neuroblastoma Trials NB90/NB95 and NB97; informed consent was obtained from each patient. The median age at diagnosis was 486 days (range, 1 day to 36 years); the median follow-up time was 3.68 years (range, 1-13.84 years). Metastatic relapses were defined as metastases in bone marrow, bone, distant lymph nodes, liver, skin, and/or other organs as defined according to the International Staging System for stage 4 (14) at any time point after diagnosis.

Alterations in chromosome arm 11q were analyzed using interphase fluorescence in situ hybridization in a dual-color procedure with DNA probes ATM (11q22.3) or MLL (11q23) in the region of interest and D11Z1 (centromere) as control (Oncor, Illkirch, France).

Two types of alterations were distinguished (according to ref. 15): deletion 11q, with only one copy of 11q22.3 (11q23) but at least two centromere copies (monosomy 11q23) and imbalance 11q, with at least two copies of 11q22.3 (11q23) with additional centromere copies.

The 11q status was defined as a loss in 11q in at least 33% of all analyzed cells. In addition, all tumors were investigated for a possible amplification of the MYCN oncogene using fluorescence in situ hybridization probes n-myc and D2Z. Amplification was defined as at least the 5-fold number of MYCN copies compared with the copy number of chromosome 2. The status of 1p was determined in 577 of 611 cases (94%; D1Z1 and D1Z2, Oncor). Between 150 and 550 nuclei (mean = 200) were counted in one tissue sample in each case.

Statistical analyses. To compare variables of interest, Fisher's exact test or {chi}2 test were used where appropriate. Kaplan-Meier estimates for event-free survival and overall survival were calculated and compared by log-rank test. For multivariate analysis, we applied Cox's proportional hazards regression model based on event-free survival. The covariates were fitted into a stepwise backward selection. The likelihood ratio test P for inclusion was <0.05 and for exclusion was >0.10.

Recurrence, progression of disease, and death from disease were counted as events. Thirteen deaths resulting from therapy complications were not counted as events but censored for event-free and overall survival analysis.


   Results
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 Abstract
 Materials and Methods
 Results
Discussion
 References
 
Alterations in distal 11q were found in 159 of 611 (26%) samples in the whole cohort. One hundred ten tumors (18%) displayed a deletion resulting in a monosomy of distal 11q, whereas 49 cases (8%) showed at least two intact copies of chromosome 11 but additional deleted copies (imbalance). The proportion of 11q alterations was relatively low in stage 1 (8%), stage 2 (10%), and stage 4S (11%) and substantially higher in stage 3 (21%). More than half of metastatic stage 4 tumors (52%) were characterized by loss of material in distal 11q (deletions and imbalances). Regarding patients age at diagnosis, we observed a discontinuous distribution of tumors with 11q alterations in different age groups. As depicted in Fig. 1 , changes in 11q were extremely rare in patients diagnosed up to 6 months (6 of 129, 5%). Between 6 months and 2.5 years, the percentage was remarkably higher but relatively constant (17-21%). The number of neuroblastomas with 11q alterations increased dramatically after the age of 2.5 up to 7 years at diagnosis (50-59%) and intriguingly decreased again over 7 years (32%). A pairwise comparison of the age groups revealed significant differences regarding age and 11q alterations (≤0.5 versus 0.5-2.5 years, P < 0.001; 0.5-2.5 versus >2.5-7 years, P < 0.001; >2.5-7 versus >7 years, P = 0.012).


Figure 1
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  		Fig. 1. Percentages of tumors showing deletion/imbalance in 11q according to different age groups.

 
Effect on patient's outcome. Patients showing a normal 11q status displayed a better outcome compared with those with either deletion or imbalance 11q. This was true for the whole cohort (event-free survival and overall survival, P < 0.001; Fig. 2A ) and for the MYCN-nonamplified cases (event-free survival and overall survival, P < 0.001; Fig. 2B). Even in the particular subgroup of MYCN-amplified tumors (MNA) of all stages, 11q status identified a subset with even worse outcome than patients with MNA alone (P = 0.03 and P = 0.02; Fig. 2C). Eleven of 13 patients in this group experienced relapses; nine of them died of disease.


Figure 2
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  		Fig. 2. Kaplan-Meier curves (event-free and overall survival) according to the status of 11q. A, whole cohort (n = 611): 3-year event-free survival (EFS): 72 ± 2% versus 46 ± 8% (imbalance) and 39 ± 5% (deletion; P < 0.0001); 3-year overall survival (OS): 87 ± 2% versus 77 ± 7% and 76 ± 4% (P < 0.0001). B, MYCN-nonamplified cohort (n = 511): 3-year event-free survival: 79 ± 2% versus 48 ± 5% and 46 ± 8% (P < 0.0001); 3-year overall survival: 94 ± 2% versus 82 ± 4% and 80 ± 7% (P < 0.0001). C, tumors with MNA (n = 100): 3-year event-free survival: 41 ± 6% versus 14 ± 9% (deletion + imbalance; P = 0.03); 3-year overall survival: 60 ± 5% versus 25 ± 8% (P = 0.02). D, stage 4 patients (n = 215): 3-year event-free survival: 35 ± 5% versus 39 ± 2% (P = not significant); 3-year overall survival: 57 ± 5% versus 70 ± 5% (P = not significant). E, stages 1 to 3 + 4S without MNA (n = 360): 3-year event-free survival: 86 ± 2% versus 46 ± 8% (P < 0.0001); 3-year overall survival: 96 ± 1% versus 93 ± 4% (P < 0.0001). F, stages 1 to 3 + 4S without MNA or 1p del (n = 313): 3-year event-free survival: 87 ± 2% versus 55 ± 9% (P < 0.0001); 3-year overall survival: 99 ± 1% versus 97 ± 3% (P = 0.0001).

 
Figure 2D shows that alterations in 11q did not allow to distinguish between outcome in patients with stage 4 disease. A clear separation between good and poor outcome, however, was observed in stage 1, 2, 3, and 4S nonamplified tumors with better prognosis for patients with intact 11q (Fig. 2E). Although the number of tumor-related deaths was fortunately low in this entity, even the overall survival was significantly different (P < 0.001). A statistical difference was furthermore observed when tumors with 1p alterations and/or MNA were excluded from the cohort of stage 1 to 3 and 4S tumors (event-free survival and overall survival, P < 0.001; Fig. 2F).

Moreover, the type of relapse in the cohort of good-risk stage 1 to 3 + 4S tumors without amplification was analyzed. Forty-five relapses were found in patients with an intact chromosome 11 (14%; Table 1A ). Most of these were locoregional; merely 9 of 45 (20%) were identified as metastatic relapses (stage 4). In contrast, the number of relapses was substantially higher in the 11q alteration group (26 relapses in 46 tumors with 11q del/imb, 57%; P < 0.0001), and the majority were progressions to stage 4 (14 of 26, 54%). The number of metastatic relapses in the MYCN-nonamplified localized and stage 4S tumors with normal 11q status was 3% (9 of 314) and significantly higher in the 11q aberration subgroup (30%, 14 of 46; P < 0.001; Table 1A and B).


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  		Table 1.

 
Finally, a multivariate analysis was done for the whole cohort, including variables stage, age, MYCN, and 11q and 1p and for the subgroup of stage 1 to 3 + 4S tumors (nonamplified), including variables age and 11q and 1p. As depicted in Table 2 in the whole cohort, all factors proved prognostic (Table 2A); in the second subset, the 11q and 1p status proved prognostic (Table 2B).


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  		Table 2. Multivariate analyses

 

   Discussion
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 Abstract
 Materials and Methods
 Results
 Discussion
References
 
During recent years, loss of material in distal chromosome 11q has evolved to one of the central cytogenetic characteristics in neuroblastoma. Evidence for its particular role in tumor development has come not only from the frequency of this aberration in primary tumors (26% in the present study) but also because constitutional 11q alterations were reported in neuroblastoma patients (16, 17). Nonconstitutional rearrangements affecting chromosome 11 often lead to the formation of a derivative chromosome 11 through unbalanced translocation with chromosome 17 as the main partner (18–21). These genomic imbalances are considered to be secondary and thus late events in oncogenesis, although there is some indication that not all chromosome 11 aberrations occur at identical periods in tumor evolution (22). In neuroblastoma, genomic changes in 11q define a particular subgroup of patients who show rarely MNA (7, 8, 11) but show a close association with other structural alterations like loss in 3p (8, 10, 23, 24) and 17q gain (10, 23). Deletions usually affect major parts of the long arm of chromosome 11. A region of interest harboring putative tumor suppressor genes is still very large, although there is some indication that 11q25 may be one of the hotspot bands (25). The number of tumors with loss in 11q was very small in patients diagnosed within the first 6 months of life but comprised the majority of children diagnosed as of the age of 2.5 years and decreased above 7 years. Most intriguingly, the proportion of 11q-deleted tumors did not increase continuously but stepwise at age 0.5, 2.5 and 7 years at diagnosis. Thus, 11q alterations are a characteristic feature of patients between 2.5 and 7 years at diagnosis. This particular age distribution underscores the opinion, that 11q alterations are probably late and mostly secondary events (22) in tumor evolution. Moreover, in contrast to MYCN-amplified tumors that may be diagnosed early due to their rapid and aggressive growths, the influence of deletions in 11q on cellular behavior is probably less strong and/or less fast. Nevertheless, in the present study, the risk estimation in different clinical subgroups clearly defined neuroblastomas with loss of material in distal 11q as high-risk tumors. The discrimination between tumors with a normal 11q status versus either deletion or imbalance 11q was statistically significant in event-free survival and overall survival regarding the whole cohort but more convincingly in the MYCN-nonamplified subset. An intriguing finding was the prognostic difference between 11q normal and deleted tumors even in the amplified subgroup. Although we could confirm previous reports about inverse correlation of MYCN amplification and 11q aberration (7, 10, 13), the rare cases in our collective (n = 13) showing both cytogenetic alterations were characterized by a dramatic decline of survival rates. Consistent with earlier data (8) from patients with metastatic stage 4 disease and a 3-year event-free survival below 40%, the 11q status is not useful to identify a favorable subset within this poor entity.

The best separation regarding the 11q status could be achieved in the subset of localized and stage 4S tumors without amplification, a group of particular interest due to a difficult risk estimation resulting in quite different therapeutic options (intermediate-risk chemotherapy versus wait-and-see strategy without chemotherapy). Although the tumor-related deaths are fortunately low in localized and stage 4S patients without MNA, even the overall survival was superior in association with a normal 11q. To avoid an overlap with 1p aberrations, we finally excluded all tumors with abnormal 1p from analyses; nonetheless, the 11q status still distinguished poor versus favorable tumors in this subset. It is noteworthy to mention that patients with localized or 4S tumors without unfavorable cytogenetic markers (MYCN amplification, deletion 1p, and deletion 11q) displayed an excellent outcome in our cohort: tumor-related deaths were nearly absent (<1%); metastatic relapses occurred in only 3% of patients; and 10% in this group experienced locoregional progressions/relapses or progressions to stage 4S.

Our investigation did not only focus on possible association between the 11q status and the number of relapses but also on the quality of events. It is of great practical importance to note that alterations in 11q do not only define a group of neuroblastomas with an increased probability of relapses in general but with a significantly higher number of metastatic relapses in particular. This has an important meaning for therapy. Our data are in very good accordance with results by Attiyeh et al. (26), comprising 11q and 1p loss of heterozygosity data from 915 patients. In their cohort, unbalanced loss of 11q and 1p proved independently prognostic for disease outcome. Consequently, they suggested the incorporation of the status of 11q and 1p in future therapy trials. The agreement between the studies despite of two different technical approaches particularly underscores the reliability of the 11q status as an important biomarker.

In the German neuroblastoma trial NB2004, aberrations in 1p already contribute to a more intensive therapy within stages 2 and 3. 11q loss is not yet part of the current risk stratification, as huge patient cohorts are necessary due to the low prevalence of cytogenetic aberrations and events in the group of localized, nonamplified neuroblastomas. However, based on the results of the present study in combination with data shown in the American cohort, it seems no longer doubtful that localized tumors with 11q alterations have a significantly increased risk for severe relapses and would most probably benefit from more intensive therapy regimens.


   Acknowledgments
 
We thank Dr. Karen Ernestus for histologic evaluation of the tissue, Joern Oestreich for excellent technical support, and Dr. André Oberthuer for many helpful discussions and critical reading of the article.


   Footnotes
 
Grant support: Deutsche Kinderkrebs-Stiftung, German Cancer Aid.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 11/16/05; revised 3/ 1/06; accepted 3/31/06.


   References
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