|Year : 2015 | Volume
| Issue : 2 | Page : 66-73
Frequency of the ALK gene and its prognostic value in neuroblastoma by FISH
Muhammad Raa'fat Khalaf, Eman Mosaad Zaki, Abeer Moustafa Darwish, Mohamed Galal Mostafa El-Naggar MD
Department of Clinical Pathology, South Egypt Cancer Institute, Assiut University, Assiut, Egypt
|Date of Submission||08-Apr-2015|
|Date of Acceptance||12-Apr-2015|
|Date of Web Publication||22-Jul-2015|
Mohamed Galal Mostafa El-Naggar
Department of Clinical Pathology, South Egypt Cancer Institute, Assiut University, Assiut 71515
Source of Support: None, Conflict of Interest: None
Introduction The anaplastic lymphoma kinase (ALK) gene has been identified as a major neuroblastoma (NB) predisposition gene. Furthermore, there are controversies on the correlation between ALK gene aberration and clinical outcome in neuroblastoma (NBL).
Materials and methods We evaluated N-MYC/ALK gene copy number by fluorescence in situ hybridization and analyzed 32 bone marrow samples infiltrated by NB and analyzed their association with the clinical outcome of the patients.
Results Although an increase in ALK gene aberration is a recurrent genetic abnormality of NB (50%, 16/32), ALK amplification was only present in one NB (3.2%, 1/32). In addition, ALK positivity also significantly correlates with N-MYC gene copy number (P < 0.000). Kaplan-Meier survival analysis indicated that the N-MYC/ALK aberration is correlated with decreased overall survival (OS) in NB. A better prognosis was observed in patients who were negative for N-MYC/ALK normal compared with those who were positive for N-MYC/ALK aberration tumors. Furthermore, ALK aberrations were significantly correlated with inferior survival in NB (P < 0.000).
Conclusion ALK aberrations in NB were correlated with advanced tumor types and an increase in both N-MYC/ALK gene aberrations. ALK aberrations predict an inferior prognosis, which can be used as a prognostic factor in NB in clinical practice.
Keywords: ALK, neuroblastoma, N-MYC
|How to cite this article:|
Khalaf MR, Zaki EM, Darwish AM, El-Naggar MM. Frequency of the ALK gene and its prognostic value in neuroblastoma by FISH. Egypt J Haematol 2015;40:66-73
|How to cite this URL:|
Khalaf MR, Zaki EM, Darwish AM, El-Naggar MM. Frequency of the ALK gene and its prognostic value in neuroblastoma by FISH. Egypt J Haematol [serial online] 2015 [cited 2020 Apr 4];40:66-73. Available from: http://www.ehj.eg.net/text.asp?2015/40/2/66/161291
| Introduction|| |
Neuroblastoma (NB) is one of the most refractory solid tumors in children, with 5-year survival rates of less than 40% following conventional treatments ,, . It is an embryonic tumor that arises from the sympathetic nervous system and represents the most frequently diagnosed malignancy in the first year of life , .
NB, the most frequent extracranial solid tumor of childhood, is characterized by wide clinical variability, with possible cellular maturation or spontaneous tumor regression, or aggressive clinical behavior with rapid progression despite intensive therapeutic approaches  . Prognosis can vary markedly, from fatal to spontaneous regression  .
Since the early 1980s, there has been significant progress in our ability to diagnose, stratify, and treat NB patients. Risk classification continues to be optimized, and clearly, future approaches will need to integrate profiling of genome copy number variations with the current International Neuroblastoma Risk Group system. This will require advances in technology that will enable the screening of patients in a time-effective, cost-efficient manner. In parallel, novel therapeutics are being developed to target key regulators of the NB genome and more refined treatment regimens are being designed on the basis of increasing knowledge of the pathogenesis of the disease. This progress is because of our increased understanding of the genetic alterations associated with tumor behavior and patient outcome  .
For years, N-MYC was the only oncogene known to be involved recurrently in ~22% of tumors, and the N-MYC protein is overexpressed by high copy number gains of the gene in tumors with advanced stages and aggressive clinical behavior ,,, .
Analysis of N-MYC remains an essential component of disease evaluation for newly diagnosed NBL patients and serves as a paradigm for the utility of molecular biologic information in cancer treatment stratification ,, . N-MYC is vital for proliferation, migration, and stem cell homeostasis, whereas decreased levels are associated with terminal neuronal differentiation  . However, downregulation of N-MYC leads to decreased proliferation and differentiation, emphasizing the importance of N-MYC signaling in NB biology , .
Anaplastic lymphoma kinase (ALK) is a membrane-associated tyrosine kinase receptor encoded by the ALK gene located in the 2p23 chromosomal region proximal to the N-MYC amplicon on 2p24.1  .
Activating point mutations in the tyrosine kinase domain of ALK, the most frequent mutations in NB, are detected at diagnosis in ~8-10% of patients and play an important role in NB oncogenesis ,,,,, .
Despite improvements in treatment over recent decades, the cure rates for patients with high-risk NB  lag significantly behind those of other common childhood cancers  . Current treatments rely on dose-intensive chemotherapy, radiation therapy, and immunotherapeutic targeting of the disialoganglioside GD2 , . The most recent clinical studies of NB have focused on escalating the dose intensity in both induction and consolidation therapies, with evidence that this improves the outcome  .
| Aim of work|| |
This work aims to assess the ALK gene and its relation to prognosis in NB patient and to determine its correlation with other clinical, morphological, or prognostic factors of the disease.
| Materials and methods|| |
Thirty-two patients admitted to the South Egypt cancer institute in the period between 2009 and 2013 diagnosed with NB on the basis of histological and immunohistochemistry examination were included in the study. All patients were subjected to a full assessment of history, assessment of family history, clinical examination, routine lab analysis, radiologic examination, and pathologic examination of the soft tissue mass with concurrent immunohistochemical studies, neuron specific enolase (NSE).
Bone marrow biopsy sections were selected from fixed and paraffin-embedded bone marrow biopsy blocks.
Probes used in this study included the N-MYC amplification probe (Cytocell Aquarius) and an ALK Dual Color Break Apart Probe (Vysis, Abbott Laboratories, Abbott Park, Illinois, USA).
The ALK dual color break-apart rearrangement probe was used to detect ALK gene rearrangements and copy number changes. This probe contains two differently labeled probes on opposite sides of the breakpoint of the ALK gene. An ~250 kb probe for the telomeric side of the ALK breakpoint is labeled with Spectrum red. The centromeric probe is ~300 kb and labeled with Spectrum Green.
The N-MYC amplification probe was used to detect N-MYC gene amplification and copy number changes. This probe contains two differently labeled probes: a 140 kb N-MYC probe labeled with red covers the N-MYC region at 2p24 and the LAF gene probe, ~201 kb and labeled with Spectrum Green, located at 2q11, acts as the control.
Interphase fluorescence in situ hybridization (FISH) was performed on 4 um-thick paraffin sections of the specimens. Briefly, the tissue sections were deparaffinized and heated in 8% sodium thiocyanate for 3 min. The sections were then digested in 0.1% of pepsin solution at 37°C for 20 min and the probe was applied onto the appropriate tissue areas. The slides were incubated at 73°C for 6 min and at 37°C for 16 h, followed by washing in gradient SSC solutions and counter-staining with anti-fade solution containing DAPI.
The slides were examined using an Axioskope 2 mot plus fluorescence Microscope (Zeiss, NY, USA) and diagnosed using image system (Leica dg software, Leica, Manhiem, Germany) Germany 2003.
In each case, around 100-200 nuclei from at least five to eight areas were examined. Nuclei with apparent overlapping or truncation were excluded from analysis. The cut-off value was established on 16 paraffin slides of the control bone marrow tissue, and was calculated as the mean (8%) plus 3 SD of nuclei counted  . All the cut-off values of the probes were less than 11%.
Normal: When hybridized with the ALK dual color break-apart rearrangement probe, the 2p23 ALK region in its native state will be seen as two immediately adjacent or fused red/green (yellow) signals. Amplification: The number of gene-specific signals is more than four times the control signals. Gain: The number of gene-specific signals is one to four times greater than the control probe signals. Loss/imbalance: Presence of one fused red/green (yellow) signals then one red and one green  .
In a normal cell, two red and two green signals are observed, whereas in cells with amplification of the N-MYC locus, multiple red signals will be observed.
| Results|| |
Our study showed that aberrant ALK genes were detected in 16/32 (50%) of cases, with amplification representing 1/32 (3.12%) (Slide 1), gain 10/32 (31.2%) (Slide 2), and loss/imbalance 5/32 (15.6%) (Slide 3). N-MYC amplification was positive in 19/32(59.3%) cases (Slide 4); the 16 cases with ALK aberration were also positive for N-MYC amplification (16/16) (100%).
Demographic data results
Clinical data in the study group showed that 62.5% were high-risk patients and 37.5% were intermediate-risk patients according to Children's Oncology Group risk groups  ; according to the International Neuroblastoma Staging System 'INSS'  , there were 75.0% in stage 4 and 25.0% in stage 4s. In terms of the International Neuroblastoma Risk Group 'INRGS' stage classification  , there were 50.0% in stage MS and 50.0% in stage M ([Table 1]).
In terms of response after 3 months according to the guidelines of International Neuroblastoma Response Criteria  , there were 28.1% no response, 18.8% mixed response (MR), 21.9% progressive disease (PD), and 31.2% partial response; whereas the 9-month follow-up showed 3.1% no response, 3.1% MR, 53.1% PD, 6.2% partial response, and 9.4% very good partial response, with 9.4% death frequency. Overall, 100% of cases were positive for NSE.
Correlation between overall survival 'OS' and other variables in the study group
There were negative correlations between OS and N.MYC quantities and ALK quantities with a highly significant difference (P < 0.000) ([Table 2] and [Figure 1], [Figure 2], [Figure 3], [Figure 4]).
|Figure 1 Kaplan-Meier curves comparing patients with and without ALK aberration (mutation, copy number gain, and/or amplification).|
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|Figure 2 Kaplan-Meier curves comparing patients with and without N-MYC amplification.|
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|Figure 3 Kaplan-Meier curves comparing patients when N-MYC aberration and ALK aberration are both negative.|
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|Figure 4 Kaplan-Meier curves comparing patients when N-MYC aberration and ALK aberration are both positive.|
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|Table 2 Correlation between overall survival 'OS' and other variables in the studied group |
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Results of ALK and N-MYC aberration
With respect to the relation between risk groups and N-MYC and ALK gene aberrations, the study group showed that 80.0% of cases in the high-risk group were qualitatively positive for the ALK gene. For quantitative results, there was an increase in the mean value of ALK-positive results in the high-risk group in comparison with the intermediate-risk group (33.10 ± 4.16 vs. 5.41 ± 0.46%), with a highly significant difference (P < 0.000) ([Table 3]).
For the N-MYC gene, 95.0% of high-risk group cases were positive for N-MYC. For quantitative results, there was an increase in the mean value of N-MYC-positive results (32.30 ± 2.53%) in the patients in the high-risk group versus (5.67 ± 0.65%) in patients in the intermediate-risk group, with a highly significant difference (P < 0.000).
|Table 3 Relation between risk group, N.MYC, and ALK in the studied group |
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Differences in disease course and overall survival among different risk groups
There was a difference in the OS between both high-risk and intermediate-risk groups, 15.35 ± 2.17 vs. 29.50 ± 4.43 months, respectively, with a significant difference (P < 0.003), ([Table 3]).
Results of the 3-month follow-up disease course
In terms of the relation between the disease course for the '3-month follow-up' of both N.MYC-positive and ALK-positive cases and OS in the group studied, ALK gene aberration showed a significant difference between disease course after 3 months (P < 0.05), with a mean value of 43.57 ± 7.42 in the PD group; 100% of cases in the PD group were positive for ALK, where N-MYC showed a highly significant difference between disease course after 3 months (P < 0.000), with a mean value of 35.42 ± 3.79 in the PD group; 100.0% of cases in the PD group were positive N.MYC quality. In terms of the OS, there were moderately significant differences (P < 0.001), with the lowest value in OS in the PD group (6.71 ± 1.37 months) ([Table 4]).
|Table 4 Relation between disease course '3m'and N.MYC, ALK, LDH, and OS in the study group |
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Results of the 9-month follow-up disease course
For the relation between disease course '9m', N.MYC, ALK, and OS in the study group, the ALK gene showed a significant difference between disease course after 9 months (P < 0.05), with a mean value of 34.10 ± 4.27 in the PD group, and 82.2% of cases in the PD group were positive for ALK, where N-MYC showed a moderately significant difference between disease course after 9 months (P < 0.00), with a mean value of 32.35 ± 2.95 in the PD group, and 94.8% of cases in PD group were positive for N.MYC. In terms of the OS, there were a moderately significant difference (P < 0.001), with the lowest value in OS in the MR group (14.00 ± 0.0 months) ([Table 5]).
|Table 5 Relation between disease course '9m'and N.MYC, ALK, LDH, and OS in the study gro |
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| Discussion|| |
Our study showed that aberrant ALK genes were detected in 16/32 (50%) of cases, with amplification representing 1/32 (3.12%), gain 10/32 (31.2%), and loss/imbalance 5/32 (15.6%). N-MYC amplifications were positive in all 19/32 (59.3%) cases; the 16 cases with ALK aberration were also positive for N-MYC amplification (16/16) (100%).
Wang et al.  detected ALK positivity in NB in 50.5% of cases, with 88% of these cases with positive N-MYC amplification.
In previous studies, ALK copy number aberrations were detected in 17-33% of tumors using locus-specific and genome-wide scanning approaches ,,,,,, . In our study, 50% of NB cases showed ALK copy number aberrations, whereas ALK amplification was detected in only one case. The case with ALK amplification also had N-MYC amplification compared with previous reports: Osajima-Hakomori et al.  1/85 (1%), in tumor tissues and 3/25 (12%) in cell lines by southern blot analysis. Caren et al.  5% in tumor tissues, Mosse et al.  , 16/491 (3.3%) of primary NBs by single nucleotide polymorphism-based microarrays, and Stock et al.  ALK amplification in one tumor and 2/13 (15%) cell line samples. Subramaniam et al.  detected amplification in 1/45 (2%) cases, whereas the FISH result of Chen et al.  showed ALK amplification in two cases [2/43(4.6%)].
Although the presence of an aberrant copy number status that included amplifications was reported to be associated with an aggressive clinical outcome , , most of the ALK amplifications co-occurred with the N-MYC amplification. A solitary amplification of ALK is so rare that it was detected previously in only two cases in separate studies , .
ALK gain noted in our study was consistent with the partial trisomy documented by single nucleotide polymorphism-based microarrays; however, our frequencies were greater than the earlier reported frequencies: 8.2% reported by Osajima-Hakomori et al.  , 112/491 (22.8%) reported by Mosse et al.  , and 2/13 (15%) of 13 (in cell lines) reported by Stock et al.  . Subramaniam et al.  reported 15/45 cases (33%), whereas Chen et al.  found ALK gain in 30/43 cases (69.7%). In a group of 22 patients with high-risk disease, George et al. detected a gain of chromosome 2p in 50% of the cases.
Loss/imbalance of the ALK gene was observed in five patients (15.6%), which is characterized by the presence of at least two ALK signals, but an increased number of control probe signals. Loss/imbalance was also observed by Subramaniam et al.  . They surmised that loss/imbalance of ALK could be attributed to a possible chromosomal duplication of the 2p23.2 region with allelic loss  .
The frequencies of N-MYC amplification (59.3%) and ALK aberration (50%) were higher than the overall frequency reported in previously published studies that screened N-MYC or ALK aberration. This could have been because study group was either stage 4 or 4s.
The survival time ranged from 3 to 48 months and the mean survival time was 22 months. N-MYC amplification is an established marker indicating aggressive tumor progression of NBL  . Our data also showed that N-MYC amplification and ALK gene aberration were correlated with decreased OS in NB.
Duijkers and colleagues , found that high ALK protein expression confers inferior survival in NB. However, Osajima-Hakomori et al.  reported that there was no significant link between ALK expression and prognosis.
Preclinical data suggest that ALK mutation and N-MYC amplification not only correlate but also synergize to initiate and promote NB genesis , . At the molecular level, ALK induces both N-MYC transcription and N-MYC protein stabilization; in turn, N-MYC increases ALK transcription  .
On the basis of the observation of Chen et al.  that N-MYC and ALK loci were localized in nuclei as separate amplicons for a single case, it was reported that ALK amplifications contribute actively toward the pathogenesis of NB rather than being secondary passenger events of MYCN amplification  .
| Conclusion|| |
In summary, using a simple and easily applicable FISH technique, we showed in the present study that ALK gene aberration and N-MYC amplification in NB are highly expressed.
ALK gene aberration is present in most NB, and its presence indicates a poor outcome. The presence of extra copies of ALK is the most common genetic aberration in NB. The ALK gene may be a good target for ALK inhibitors in the treatment of NB.
| Acknowledgements|| |
This work was supported by the South Egypt Cancer Institute.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]