Chromosome 1p and 11q Deletions and Outcome in Neuroblastoma
Edward F. Attiyeh, M.D., Wendy B. London, Ph.D., Yael P. Mossé, M.D., Qun Wang, M.D., Ph.D., Cynthia Winter, B.A., Deepa Khazi, M.S., Patrick W. McGrady, M.S., Robert C. Seeger, M.D., A. Thomas Look, M.D., Hiroyuki Shimada, M.D., Garrett M. Brodeur, M.D., Susan L. Cohn, M.D., Katherine K. Matthay, M.D., John M. Maris, M.D., for the Children's Oncology Group
Background Neuroblastoma is a childhood cancer with considerablemorbidity and mortality. Tumor-derived biomarkers may improverisk stratification.
Methods We screened 915 samples of neuroblastoma for loss ofheterozygosity (LOH) at chromosome bands 1p36 and 11q23. Additionalanalyses identified a subgroup of cases of 11q23 LOH with unbalanced11q LOH (unb11q LOH; defined as loss of 11q with retention of11p). The associations of LOH with relapse and survival weredetermined.
Results LOH at 1p36 was identified in 209 of 898 tumors (23percent) and LOH at 11q23 in 307 of 913 (34 percent). Unb11qLOH was found in 151 of 307 tumors with 11q23 LOH (17 percentof the total cohort). There was a strong association of 1p36LOH, 11q23 LOH, and unb11q LOH with most high-risk disease features(P<0.001). LOH at 1p36 was associated with amplificationof the MYCN oncogene (P<0.001), but 11q23 LOH and unb11qLOH were not (P<0.001 and P=0.002, respectively). Cases withunb11q LOH were associated with three-year event-free and overallsurvival rates (±SE) of 50±5 percent and 66±5percent, respectively, as compared with 74±2 percentand 83±2 percent among cases without unb11q LOH (P<0.001for both comparisons). In a multivariate model, unb11q LOH wasindependently associated with decreased event-free survival(P=0.009) in the entire cohort, and both 1p36 LOH and unb11qLOH were independently associated with decreased progression-freesurvival in the subgroup of patients with features of low-riskand intermediate-risk disease (P=0.002 and P=0.02, respectively).
Conclusions Unb11q LOH and 1p36 LOH are independently associatedwith a worse outcome in patients with neuroblastoma.
Neuroblastoma is a cancer of early childhood in which genomicchanges in the tumor correlate with its behavior and outcomein patients.1,2 The algorithm devised by the Children's OncologyGroup for risk assessment in cases of neuroblastoma has beensuccessful in distinguishing patients with aggressive diseasefrom those with a high likelihood of cure after surgery or evenobservation alone. The algorithm stratifies patients into threesubgroups with expected low, intermediate, and high risks ofdeath from neuroblastoma. This system involves the use of theclinical factors of age at diagnosis, tumor stage, and the resultsof the Shimada method of histopathological classification, aswell as the biologic factors of amplification status of theMYCN oncogene and DNA index.1 Amplification of MYCN, which playsa critical part in neurodevelopment and occurs in about 20 percentof cases of neuroblastoma, was one of the first tumor-derivedgenetic markers that was shown to be of clinical value, andit continues to provide important prognostic information.
Whereas patients in the low-risk subgroup have an overall survivalrate of more than 95 percent,3 patients in the high-risk subgrouphave a rate of long-term survival of less than 40 percent despitedose-intensive, multimodal therapy.4,5,6 These differences reflectthe heterogeneity of neuroblastoma. For example, many high-risktumors have MYCN amplification, but more than 60 percent donot,7 suggesting that there are other genetic pathways in thedevelopment of high-risk neuroblastoma.
Loss of heterozygosity (LOH; loss of one allele at a polymorphiclocus) at chromosome arms 1p and 11q occurs frequently in neuroblastoma.8,9,10,11,12Previous studies have suggested that there is an associationbetween LOH at 1p36 or 11q23 and features of high-risk neuroblastoma.8,9,10,11,13,14Whereas 1p36 LOH was found to be associated with MYCN amplification,11q23 LOH was rarely observed in tumors with this abnormality.8,14An independent association of 1p36 LOH with decreased event-freesurvival has also been reported, but these studies did not includeall of the prognostic factors currently in use.9,13 Given that11q23 LOH occurs primarily in tumors without MYCN amplification,we hypothesized that 11q23 LOH could be a useful prognosticmarker, especially in cases defined as associated with low orintermediate risk. Therefore, we determined the allelic statusat chromosome arms 1p and 11q in a large series of neuroblastomasaccrued from recent cooperative-group clinical trials.
Methods
Study Design and Patients
Eligible patients were those in whom a diagnosis of neuroblastomahad been made between July 1985 and July 2003 and who were registeredfor a biology study with the Children's Cancer Group (CCG B973),the Pediatric Oncology Group (POG 9047), or the Children's OncologyGroup (COG ANBL00B1). The only inclusion criteria were the availabilityof outcome data and both tumor and nontumor genomic DNA. Tumorswere classified according to the International NeuroblastomaStaging System (INSS).15 Treatment was assigned according torisk group on the basis of evaluation of the patient's age atdiagnosis and the INSS stage and MYCN-amplification status ofthe tumor. Other covariables included the Shimada histopathologicalcategory and the DNA index (described below). In general, patientswith low-risk disease (INSS stages 1, 2, and 4S) were treatedwith surgery or observation only.3,16,17,18 Patients with intermediate-riskdisease (those with biologically favorable stage 3 tumors andinfants with stage 4 tumors and nonamplified MYCN) were treatedwith surgery and adjuvant chemotherapy of moderate intensity.19High-risk patients (those with biologically unfavorable stage3 tumors, infants with stage 4 tumors and amplified MYCN, andall patients one year of age or older with stage 4 tumors) weretreated with neoadjuvant regimens of dose-intensive inductionchemotherapy with alkylating agents and platinum, delayed resectionof the primary tumor, radiation therapy at the primary tumorsite, and in most patients, a regimen of myeloablative consolidationchemotherapy followed by autologous stem-cell rescue.4
The institutional review board of the Children's Hospital ofPhiladelphia approved this study, and investigators at all participatinginstitutions obtained informed consent for a biologic studybefore specimens were obtained.
Samples and Biologic Studies
Immediately after surgical removal, tumor samples were snap-frozenor placed in tissue-culture media and shipped to a central referencelaboratory for studies of tumor biology. The amplification statusof MYCN was determined with the use of immunohistochemical analysis,20fluorescence in situ hybridization,21 or Southern blotting.22Histopathological analysis was performed according to centralreview with the use of the method of Shimada and colleagues.23The DNA index was defined with the use of flow cytometry, aspreviously described.24 DNA from the tumor and blood or uninvolvedbone marrow was prepared with the use of anion-exchange chromatography(Qiagen).
Allelic Status of Chromosome Arms 1p and 11q
We first screened tumor samples for LOH at 1p36 and 11q23 usinga panel of fluorescently labeled microsatellite markers, aspreviously described (chromosome 1: D1S243, D1S468, D1S2145,D1S1646, D1S3720, and GGAA30B06; chromosome 11: D11S1760, D11S1338,D11S4090, D11S908, D11S4127, D11S925, D11S4094, and D11S4191).8,9,12When possible, markers were combined in multiplex fluorescencescreening panels. Samples for which there were equivocal resultsunderwent repeated screening in a conventional uniplex polymerasechain reaction (PCR). Individual samples were analyzed withup to 35 additional markers for chromosome arm 1p and 59 additionalmarkers for chromosome 11 (Table 1 of the Supplementary Appendix,available with the full text of this article at www.nejm.org)to confirm LOH status and map the region of deletion. Electrophoresiswas performed with the use of a DNA-sequencing instrument (PerkinElmer–AppliedBiosystems; model 377 or 3730) and analyzed with ABI softwarepackages (GeneScan with Genotyper or GeneMapper). LOH at anindividual marker was considered to be present when a comparisonof the allelic intensity of fluorescence electropheretogramsyielded a score of less than 0.5 or more than 2.0 (indicatinga 50 percent reduction in intensity of one tumor allele), aspreviously described.8,9,12 A sample was considered to haveLOH at 1p36 or 11q23 if there were at least two informativemarkers at that locus showing LOH. During the assessment ofallelic status, investigators were blinded to the characteristicsof the patients and to outcome data.
We distinguished among samples with LOH at every marker alongchromosome 11 (referred to as whole-chromosome 11 LOH) and sampleswith LOH at markers on 11q with retention of 11p material (referredto as unbalanced LOH, or unb11q LOH). The assignment of thestatus of whole-chromosome 11 LOH and unb11q LOH required thepresence of at least two informative markers on 11p or proximal11q in addition to the two or more informative markers at 11q23.This distinction was not relevant for chromosome 1, becausethe deletion of this entire chromosome was essentially neverobserved in our earlier work or in the extensive literatureon comparative genomic hybridization.25,26
Statistical Analysis
Tests of association were performed with the use of Fisher'sexact test. Survival curves were constructed according to themethods of Kaplan and Meier,27 with standard errors accordingto the method of Peto,28 and comparisons of the survival curveswere performed with a two-sided log-rank test. Failures, orevents, for the event-free survival analysis were defined asrelapse, disease progression, a secondary cancer, or death.Events for the progression-free survival analysis were definedas relapse or disease progression. The time to an event wascalculated as the time from study enrollment to the occurrenceof the first event or the time to the last contact with thepatient if no event occurred. The time to an event for the overallsurvival analysis was calculated as the time from study enrollmentuntil the time of death or the time of last contact if the patientwas alive. Event-free survival, progression-free survival, andoverall survival rates were calculated as the rates ±SE.
Multivariate analyses were performed with the use of a Cox proportional-hazardsregression model29 to identify variables that were independentlypredictive of outcome. A stepwise, backward model-building procedurewas used to identify the variables retained in the Cox model,with a P value of less than 0.05 considered to indicate statisticalsignificance. The patient cohort analyzed in each model wasmade up of all patients for whom complete data were availablefor the variables in the model.
Results
Characteristics of the Patients
Clinicopathological characteristics of the patients and thetumors are detailed in Table 1. The cohort we studied was representativeof the population with neuroblastoma as a whole.7 With a medianfollow-up of 3.01 years, the three-year event-free and overallsurvival rates (±SE) for the entire cohort were 70±2percent and 89±2 percent, respectively. A risk groupcould not be assigned in 29 cases owing to missing data.
Table 1. Number and Proportion of Patients with 1p36 LOH, 11q23 LOH, and unb11q LOH, According to Characteristics of Patients and Tumors.
Frequency and Distribution of 1p36 and 11q23 LOH
LOH at chromosome arm 1p was detected in 209 samples (23 percent)(Table 1), with a common region of deletion at 1p36.3.12 Therewere significant associations between 1p36 LOH and the presenceof the adverse prognostic factors age of 365 days or more (P<0.001),INSS stage 4 disease (P<0.001), MYCN amplification (P<0.001),unfavorable Shimada histologic category (P<0.001), diploidy(P=0.001), and high-risk Children's Oncology Group status (P<0.001).
LOH at chromosome band 11q23 was detected in 307 samples (34percent) (Table 1 and Figure 1). Unb11q LOH was present in 151samples (50 percent of those with 11q23 LOH; 4 cases could notbe classified). The pattern of LOH for each tumor sample wasconsistent with the presence of a single region of deletion.All but three deletions included chromosome band 11q23; allbut five overlapped with the previously implicated region within11q23.3.8
Figure 1. Electropherograms Representing Loss of Heterozygosity (LOH) of Chromosome 11.
The patterns shown represent no LOH (Panel A), unbalanced 11q LOH (with retention of 11p material) (Panel B), and whole-chromosome 11 LOH (Panel C).
LOH at chromosome band 11q23 (without regard to 11p material[307 cases]) was significantly associated with the presenceof the adverse prognostic factors of INSS stage 4 disease (P<0.001)and unfavorable Shimada histologic category (P=0.002) but alsowith the favorable prognostic factor of hyperdiploidy (P=0.007)(Table 1). The subgroup of these cases defined as unb11q LOH(151 cases) had significant associations with the presence ofthe adverse prognostic factors age of 365 days or more (P<0.001),INSS stage 4 disease (P<0.001), and unfavorable Shimada histologiccategory (P<0.001). Both the 11q23 LOH group and the unb11qLOH subgroup were significantly associated with tumors thatdid not have MYCN amplification (P<0.001 and P=0.002, respectively).
Effect of 1p36 and 11q23 LOH on Patients' Outcomes
A univariate analysis of patients' outcomes showed that LOHat chromosome band 1p36 was significantly associated with adecreased probability of survival. Patients in whom tumors showed1p36 LOH had three-year event-free and overall survival ratesof 47±4 percent and 64±4 percent, respectively,as compared with 77±2 percent (P<0.001) and 85±2percent (P<0.001), respectively, in patients in whom tumorsdid not have 1p36 LOH (Table 2 and Figure 2A and Figure 2B).
Figure 2. Event-free and Overall Survival According to 1p36 Loss of Heterozygosity (LOH).
The rates of event-free and overall survival are shown for all patients (Panels A and B), event-free and overall survival for those whose tumors did not have MYCN amplification (Panels C and D), and event-free survival for those with low-risk disease, as defined by the Children's Oncology Group (COG) (Panel E), and intermediate-risk disease (Panel F). The numbers of patients at risk for an event are shown along the curves. Two-sided P values were calculated with the use of the log-rank test.
As compared with cases in which 11q23 LOH was not found, caseswith 11q23 LOH (without regard to 11p material) were associatedwith a decreased probability of event-free survival (63±3percent vs. 74±3 percent, P=0.003); the difference inoverall survival (77±3 percent vs. 82±2 percent)however, was not statistically significant (P=0.07). Unb11qLOH (151 cases) was strongly associated with both decreasedevent-free and decreased overall survival (Figure 3A and Figure 3B).Patients whose tumors showed unb11q LOH had three-yearevent-free and overall survival rates of 50±5 percentand 66±5 percent, respectively, as compared with 74±2percent (P<0.001) and 83±2 percent (P<0.001) inthe group that did not have unb11q LOH (Table 2).
Figure 3. Event-free and Overall Survival According to Unbalanced 11q Loss of Heterozygosity (unb11q LOH).
The rates of event-free and overall survival are shown for all patients (Panels A and B), event-free and overall survival for those whose tumors did not have MYCN amplification (Panels C and D), and event-free survival for those with low-risk disease, as defined by the Children's Oncology Group (COG) (Panel E) and intermediate-risk disease (Panel F). The numbers of patients at risk for an event are shown along the curves. Two-sided P values were calculated with the use of the log-rank test.
In 40 cases, both 1p36 and unb11q LOH were detected. The patientswith these tumors had a three-year event-free survival rateof 36±10 percent; the 274 cases with only one or theother aberration had a three-year event-free survival rate of52±4 percent (P=0.10).
Analysis of the subgroup of cases without amplification of MYCNshowed that both 1p36 LOH and unb11q LOH were highly associatedwith decreases in both event-free survival (P<0.001 for both)and overall survival (P=0.05 and P<0.001, respectively) (Table 2and Figure 2C, Figure 2D, Figure 3C, and Figure 3D). Withinthe risk groups defined by the Children's Oncology Group, 1p36LOH was associated with shortened event-free survival amonglow-risk patients, whereas unb11q LOH was associated with shortenedevent-free survival within both the low-risk and intermediate-riskgroups (Table 3 and Figure 2E, Figure 2F, Figure 3E, and Figure 3F).We also analyzed progression-free survival in these cohorts.The three-year progression-free survival rate for low-risk andintermediate-risk patients combined was 73±8 percentfor those with 1p36 LOH, as compared with 91±2 percentfor those without it (P=0.002); the progression-free survivalrate was 75±10 percent for patients with unb11q LOH,as compared with 90±2 percent for patients without it(P=0.006) (Table 3, and Figure 1 of the Supplementary Appendix).The differences in overall survival rates among patients withand without unb11q LOH within both of these groups were notstatistically significant (P=0.09 and P=0.15) (Table 3).
Table 3. Univariate Analysis of Event-free, Overall, and Progression-free Survival Rates According to the Clinical Risk Groups.
In a multivariate analysis, unb11q LOH was found to be independentlyassociated with decreased event-free survival (Table 4). INSSstage 4 disease, MYCN amplification, and an unfavorable Shimadahistologic category were also independently significant in thismodel. The age of the patient, the DNA index, 1p36 LOH, and11q23 LOH without regard to 11p material (307 patients) werenot independently associated with event-free survival. Unb11qLOH was not significantly associated with overall survival afteradjustment for INSS stage 4 disease, MYCN amplification, unfavorableShimada histologic category, and DNA index; however, there wasa trend toward independent significance with unb11q LOH thatwas not seen with 1p36 LOH. In low-risk and intermediate-riskpatients, MYCN amplification, an unfavorable Shimada histologiccategory, unb11q LOH, and 1p36 LOH were all independently associatedwith decreased progression-free survival (Table 5).
Table 5. Results of Multivariate Cox Model of Progression-free Survival in 492 Low-Risk and Intermediate-Risk Patients for Whom Complete Data Were Available.
Discussion
The ability to detect risk factors at diagnosis and tailor therapyaccordingly could make the treatment of cancer more effectiveand less toxic than it has been. Among these risk factors aretumor-cell markers, of which MYCN amplification, HER2/neu overexpression,and certain translocations (e.g., BCR-ABL, PAX-FKHR) have proveduseful. Our findings regarding the association of 1p36 and unb11qLOH with the survival of children with neuroblastoma suggestthat these variables should be incorporated into clinical trials.
Although MYCN amplification is a hallmark of aggressive diseasein patients with neuroblastoma, 60 percent of high-risk tumorsdo not have this aberration. Furthermore, aggressive diseasewill ultimately develop in a subgroup of patients within thelow-risk and intermediate-risk groups despite the lack of MYCNamplification. Since 11q23 LOH occurs almost exclusively intumors without MYCN amplification, we postulated that it maybe a useful marker for tumors that are aggressive but lack MYCNamplification. The decreased probability of survival associatedwith unb11q LOH should be considered in the light of the tendencyof 11q23 LOH to occur in tumors without MYCN amplification.In fact, the proportion of patients whose tumors had MYCN amplificationwas higher in the subgroup of 750 patients (133 patients; 18percent) who did not have unb11q LOH (and who had a better overalloutcome) than in the subgroup of 149 patients (12 patients;8 percent) who had unb11q LOH (and had a worse outcome) (P=0.002).
The lack of MYCN amplification in tumors with 11q23 LOH contrastswith the findings regarding 1p36 LOH. Although 1p36 LOH washighly associated with a decreased probability of survival,there was a statistically significant overlap between tumorswith 1p36 LOH and tumors with MYCN amplification.9,13 The associationbetween 1p36 LOH and MYCN amplification may partially explainwhy 1p36 LOH was not independently associated with survivalafter the adjustment for MYCN amplification in multivariateanalyses. After the multivariate model was restricted to thelow-risk and intermediate-risk groups, which are made up almostentirely of patients with tumors that do not have MYCN amplification,1p36 LOH was independently associated with progression-freesurvival, confirming our previous report.9
We distinguished tumors showing unb11q LOH from those in whichevery marker on chromosome 11 showed LOH, because hyperdiploidDNA content is common in neuroblastoma and presumably resultsfrom a defect in the mitotic machinery that causes random gainsand losses of whole chromosomes.1,2 This defect can result inmonosomy for chromosome 11 or in multiple copies of one parentallyderived homologue that can masquerade, in a PCR-based assay,as LOH. Thus, we excluded these cases because we concluded thatthey probably differed from those in the subgroup that had atargeted deletion. Data from conventional and array-based comparativegenomic hybridization had previously shown that loss of theentire chromosome 1 does not occur,25,26 and therefore, in thisstudy, the distinction was relevant only to chromosome 11. Ourfindings strongly suggest that future applications of the resultsof this research to the treatment of neuroblastoma will requirea global assessment of the status of LOH for chromosome 11 inorder to maximize prognostic power. An assessment of whole-genomeLOH and copy number, with the use of array-based probes, wouldresult in a higher-throughput assessment of the complex genomicpatterns present in neuroblastomas and their associations withclinical phenotype.
We have shown that 1p36 LOH and unb11q LOH are strongly associatedwith outcome in patients with neuroblastoma. The addition ofthese markers to the currently used prognostic variables mayallow for more precise treatment recommendations. For example,because both 1p and unb11q LOH are independently predictiveof worse progression-free survival in patients with low-riskand intermediate-risk disease, the Children's Oncology Groupplans to use these markers to assign the number of cycles ofadjuvant chemotherapy in the hope of averting a relapse of disease.The effect of unb11q LOH with regard to overall survival inthese subgroups was of borderline significance; however, thenumbers within each subgroup are small, and future analyseswith longer follow-up times are required. Further studies mayultimately show that certain low-risk patients with 1p36 LOH,unb11q LOH, or both, who are currently treated with surgeryalone would benefit from adjuvant chemotherapy.
We do not know whether 1p36 LOH and unb11q LOH can facilitatethe assignment of treatment for patients with high-risk disease.Recent data suggest that the prognostic effect of age is continuousin nature, and the Children's Oncology Group now recommendschemotherapy of decreased intensity for patients between 12and 18 months of age who have metastatic disease with "biologicallyfavorable" tumors.30 Future clinical trials involving patientswith high-risk neuroblastomas may be designed to stratify treatmentintensity on the basis of aberrations in MYCN, 1p, 11q, othergenomic loci such as 3p or 17q, or all of these, which are currentlyunder study by the Children's Oncology Group. It is expectedthat the pattern of genomic aberrations present in the cancercell, rather than any individual marker, will provide the mostsensitive and specific prognostic information.
In summary, we have shown that 1p36 LOH is present in about23 percent of primary neuroblastomas, is highly associated inunivariate analyses with a poor outcome, and is independentlypredictive of worse progression-free survival in low-risk andintermediate-risk patients. We have also shown that unb11q LOHis present in about 17 percent of primary neuroblastomas, predominantlyin those without MYCN amplification, and that this LOH is anindependently significant marker of decreased event-free andprogression-free survival. The clinical usefulness identificationof 1p36 LOH and unb11q LOH is currently applicable to patientswith localized disease whose tumors do not show MYCN amplification,since patients with metastatic disease, MYCN amplification,or both, for the most part already receive the most aggressivetherapy.
Supported in part by grants (R01-CA87847 and U10-CA78966, toDr. Maris; and R01-CA39771, to Dr. Brodeur, and U10-CA98543,to the Children's Oncology Group) from the National Institutesof Health; and by the National Childhood Cancer Foundation,the Alex's Lemonade Stand Foundation, the Hope Street Kids Foundation,and the Abramson Family Cancer Research Institute (all to Dr.Maris).
Presented in part at the 41st annual meeting of the AmericanSociety of Clinical Oncology, Orlando, Fla., May 13–17,2005.
Source Information
From Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, and Abramson Family Cancer Research Institute, Philadelphia (E.F.A., Y.P.M., Q.W., C.W., D.K., G.M.B., J.M.M.); the Children's Oncology Group, Arcadia, Calif. (E.F.A., W.B.L., Y.P.M., Q.W., D.K., P.W.M., R.C.S., A.T.L., H.S., G.M.B., S.L.C., K.K.M., J.M.M.); the Department of Statistics, University of Florida, and Children's Oncology Group, Gainesville (W.B.L., P.W.M.); Children's Hospital of Los Angeles, Los Angeles (R.C.S., H.S.); Dana–Farber Cancer Institute, Harvard Medical School, Boston (A.T.L.); the Feinberg School of Medicine, Northwestern University, Chicago (S.L.C.); and the University of California, San Francisco, School of Medicine, San Francisco (K.K.M.).
Address reprint requests to Dr. Maris at the Division of Oncology, Children's Hospital of Philadelphia, Abramson Pediatric Research Center 902A, 3615 Civic Center Blvd., Philadelphia, PA 19104-4318, or at maris{at}email.chop.edu.
References
Maris JM. The biologic basis for neuroblastoma heterogeneity and risk stratification. Curr Opin Pediatr 2005;17:7-13. [CrossRef][Medline]
Perez CA, Matthay KK, Atkinson JB, et al. Biologic variables in the outcome of stages I and II neuroblastoma treated with surgery as primary therapy: a Children's Cancer Group study. J Clin Oncol 2000;18:18-26. [Free Full Text]
Matthay KK, Villablanca JG, Seeger RC, et al. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. N Engl J Med 1999;341:1165-1173. [Free Full Text]
Simon T, Hero B, Faldum A, et al. Consolidation treatment with chimeric anti-GD2-antibody ch14.18 in children older than 1 year with metastatic neuroblastoma. J Clin Oncol 2004;22:3549-3557. [Free Full Text]
Pritchard J, Cotterill SJ, Germond SM, Imeson J, de Kraker J, Jones DR. High dose melphalan in the treatment of advanced neuroblastoma: results of a randomised trial (ENSG-1) by the European Neuroblastoma Study Group. Pediatr Blood Cancer 2005;44:348-357. [Medline]
Brodeur GM, Maris JM. Neuroblastoma. In: Pizzo PA, Poplack DG, eds. Principles and practice of pediatric oncology. 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2002:895-938.
Guo C, White PS, Weiss MJ, et al. Allelic deletion at 11q23 is common in MYCN single copy neuroblastomas. Oncogene 1999;18:4948-4957. [CrossRef][Web of Science][Medline]
Maris JM, Weiss MJ, Guo C, et al. Loss of heterozygosity at 1p36 independently predicts for disease progression but not decreased overall survival probability in neuroblastoma patients: a Children's Cancer Group study. J Clin Oncol 2000;18:1888-1899. [Free Full Text]
Luttikhuis ME, Powell JE, Rees SA, et al. Neuroblastomas with chromosome 11q loss and single copy MYCN comprise a biologically distinct group of tumours with adverse prognosis. Br J Cancer 2001;85:531-537. [CrossRef][Medline]
Spitz R, Hero B, Ernestus K, Berthold F. Deletions in chromosome arms 3p and 11q are new prognostic markers in localized and 4s neuroblastoma. Clin Cancer Res 2003;9:52-58. [Free Full Text]
White PS, Thompson PM, Gotoh T, et al. Definition and characterization of a region of 1p36.3 consistently deleted in neuroblastoma. Oncogene 2005;24:2684-2694. [CrossRef][Web of Science][Medline]
Caron H, van Sluis P, de Kraker J, et al. Allelic loss of chromosome 1p as a predictor of unfavorable outcome in patients with neuroblastoma. N Engl J Med 1996;334:225-230. [Free Full Text]
Maris JM, Guo C, White PS, et al. Allelic deletion at chromosome bands 11q14-23 is common in neuroblastoma. Med Pediatr Oncol 2001;36:24-27. [CrossRef][Medline]
Brodeur GM, Pritchard J, Berthold F, et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 1993;11:1466-1477. [Free Full Text]
Katzenstein HM, Bowman LC, Brodeur GM, et al. Prognostic significance of age, MYCN oncogene amplification, tumor cell ploidy, and histology in 110 infants with stage D(S) neuroblastoma: the Pediatric Oncology Group experience -- a Pediatric Oncology Group study. J Clin Oncol 1998;16:2007-2017. [Abstract]
Alvarado CS, London WB, Look AT, et al. Natural history and biology of stage A neuroblastoma: a Pediatric Oncology Group study. J Pediatr Hematol Oncol 2000;22:197-205. [CrossRef][Medline]
Nickerson HJ, Matthay KK, Seeger RC, et al. Favorable biology and outcome of stage IV-S neuroblastoma with supportive care or minimal therapy: a Children's Cancer Group study. J Clin Oncol 2000;18:477-486. [Free Full Text]
Matthay KK, Perez C, Seeger RC, et al. Successful treatment of stage III neuroblastoma based on prospective biologic staging: a Children's Cancer Group study. J Clin Oncol 1998;16:1256-1264. [Free Full Text]
Seeger RC, Wada R, Brodeur GM, et al. Expression of N-myc by neuroblastomas with one or multiple copies of the oncogene. Prog Clin Biol Res 1988;271:41-49. [Medline]
Mathew P, Valentine MB, Bowman LC, et al. Detection of MYCN gene amplification in neuroblastoma by fluorescence in situ hybridization: a Pediatric Oncology Group study. Neoplasia 2001;3:105-109. [CrossRef][Medline]
Seeger RC, Brodeur GM, Sather H, et al. Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. N Engl J Med 1985;313:1111-1116. [Abstract]
Shimada H, Chatten J, Newton WA Jr, et al. Histopathologic prognostic factors in neuroblastic tumors: definition of subtypes of ganglioneuroblastoma and an age-linked classification of neuroblastomas. J Natl Cancer Inst 1984;73:405-416. [Web of Science][Medline]
Look AT, Hayes FA, Shuster JJ, et al. Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma: a Pediatric Oncology Group Study. J Clin Oncol 1991;9:581-591. [Abstract]
Mosse YP, Greshock J, Margolin A, et al. High-resolution detection and mapping of genomic DNA alterations in neuroblastoma. Genes Chromosomes Cancer 2005;43:390-403. [CrossRef][Medline]
Plantaz D, Mohapatra G, Matthay KK, Pellarin M, Seeger RC, Feuerstein BG. Gain of chromosome 17 is the most frequent abnormality detected in neuroblastoma by comparative genomic hybridization. Am J Pathol 1997;150:81-89. [Abstract]
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-481. [CrossRef][Web of Science]
Peto R, Peto J. Asymptotically efficient rank invariant test procedures. J R Stat Soc [A] 1972;135:185-98.
Cox DR. Regression models and life-tables. J R Stat Soc [B] 1972;34:187-220.
London WB, Castleberry RP, Matthay KK, et al. Evidence for an age cut-off greater than 365 days for neuroblastoma risk group stratification in the Children's Oncology Group (COG). J Clin Oncol 2005;353:1459-1465.
Forloni, M., Albini, S., Limongi, M. Z., Cifaldi, L., Boldrini, R., Nicotra, M. R., Giannini, G., Natali, P. G., Giacomini, P., Fruci, D.
(2010). NF-{kappa}B, and not MYCN, Regulates MHC Class I and Endoplasmic Reticulum Aminopeptidases in Human Neuroblastoma Cells. Cancer Res.
70: 916-924
[Abstract][Full Text]
Mullassery, D, Dominici, C, Jesudason, E C, McDowell, H P, Losty, P D
(2009). Neuroblastoma: contemporary management. EDUCATION AND PRACTICE
94: 177-185
[Full Text]
Lagmay, J. P., London, W. B., Gross, T. G., Termuhlen, A., Sullivan, N., Axel, A., Mundy, B., Ranalli, M., Canner, J., McGrady, P., Hall, B.
(2009). Prognostic Significance of Interleukin-6 Single Nucleotide Polymorphism Genotypes in Neuroblastoma: rs1800795 (Promoter) and rs8192284 (Receptor). Clin. Cancer Res.
15: 5234-5239
[Abstract][Full Text]
Volchenboum, S. L., Li, C., Li, S., Attiyeh, E. F., Reynolds, C. P., Maris, J. M., Look, A. T., George, R. E.
(2009). Comparison of Primary Neuroblastoma Tumors and Derivative Early-Passage Cell Lines Using Genome-Wide Single Nucleotide Polymorphism Array Analysis. Cancer Res.
69: 4143-4149
[Abstract][Full Text]
Pezzolo, A., Rossi, E., Gimelli, S., Parodi, F., Negri, F., Conte, M., Pistorio, A., Sementa, A., Pistoia, V., Zuffardi, O., Gambini, C.
(2009). Presence of 1q gain and absence of 7p gain are new predictors of local or metastatic relapse in localized resectable neuroblastoma. Neuro Oncology
11: 192-200
[Abstract][Full Text]
Janoueix-Lerosey, I., Schleiermacher, G., Michels, E., Mosseri, V., Ribeiro, A., Lequin, D., Vermeulen, J., Couturier, J., Peuchmaur, M., Valent, A., Plantaz, D., Rubie, H., Valteau-Couanet, D., Thomas, C., Combaret, V., Rousseau, R., Eggert, A., Michon, J., Speleman, F., Delattre, O.
(2009). Overall Genomic Pattern Is a Predictor of Outcome in Neuroblastoma. JCO
27: 1026-1033
[Abstract][Full Text]
Schulte, J. H., Lim, S., Schramm, A., Friedrichs, N., Koster, J., Versteeg, R., Ora, I., Pajtler, K., Klein-Hitpass, L., Kuhfittig-Kulle, S., Metzger, E., Schule, R., Eggert, A., Buettner, R., Kirfel, J.
(2009). Lysine-Specific Demethylase 1 Is Strongly Expressed in Poorly Differentiated Neuroblastoma: Implications for Therapy. Cancer Res.
69: 2065-2071
[Abstract][Full Text]
Attiyeh, E. F., Diskin, S. J., Attiyeh, M. A., Mosse, Y. P., Hou, C., Jackson, E. M., Kim, C., Glessner, J., Hakonarson, H., Biegel, J. A., Maris, J. M.
(2009). Genomic copy number determination in cancer cells from single nucleotide polymorphism microarrays based on quantitative genotyping corrected for aneuploidy. Genome Res
19: 276-283
[Abstract][Full Text]
Bagatell, R., Beck-Popovic, M., London, W. B., Zhang, Y., Pearson, A. D.J., Matthay, K. K., Monclair, T., Ambros, P. F., Cohn, S. L.
(2009). Significance of MYCN Amplification in International Neuroblastoma Staging System Stage 1 and 2 Neuroblastoma: A Report From the International Neuroblastoma Risk Group Database. JCO
27: 365-370
[Abstract][Full Text]
Cohn, S. L., Pearson, A. D.J., London, W. B., Monclair, T., Ambros, P. F., Brodeur, G. M., Faldum, A., Hero, B., Iehara, T., Machin, D., Mosseri, V., Simon, T., Garaventa, A., Castel, V., Matthay, K. K.
(2009). The International Neuroblastoma Risk Group (INRG) Classification System: An INRG Task Force Report. JCO
27: 289-297
[Abstract][Full Text]
Yagyu, S., Gotoh, T., Iehara, T., Miyachi, M., Katsumi, Y., Tsubai-Shimizu, S., Kikuchi, K., Tamura, S., Tsuchiya, K., Imamura, T., Misawa-Furihata, A., Sugimoto, T., Sawada, T., Hosoi, H.
(2008). Circulating Methylated-DCR2 Gene in Serum as an Indicator of Prognosis and Therapeutic Efficacy in Patients with MYCN Nonamplified Neuroblastoma. Clin. Cancer Res.
14: 7011-7019
[Abstract][Full Text]
Oberthuer, A., Kaderali, L., Kahlert, Y., Hero, B., Westermann, F., Berthold, F., Brors, B., Eils, R., Fischer, M.
(2008). Subclassification and Individual Survival Time Prediction from Gene Expression Data of Neuroblastoma Patients by Using CASPAR. Clin. Cancer Res.
14: 6590-6601
[Abstract][Full Text]
Fredlund, E., Ringner, M., Maris, J. M., Pahlman, S.
(2008). High Myc pathway activity and low stage of neuronal differentiation associate with poor outcome in neuroblastoma. Proc. Natl. Acad. Sci. USA
105: 14094-14099
[Abstract][Full Text]
Bilke, S., Chen, Q.-R., Wei, J. S., Khan, J.
(2008). Whole Chromosome Alterations Predict Survival in High-Risk Neuroblastoma without MYCN Amplification. Clin. Cancer Res.
14: 5540-5547
[Abstract][Full Text]
Fujita, T., Igarashi, J., Okawa, E. R., Gotoh, T., Manne, J., Kolla, V., Kim, J., Zhao, H., Pawel, B. R., London, W. B., Maris, J. M., White, P. S., Brodeur, G. M.
(2008). CHD5, a Tumor Suppressor Gene Deleted From 1p36.31 in Neuroblastomas. JNCI J Natl Cancer Inst
100: 940-949
[Abstract][Full Text]
Maris, J. M., Mosse, Y. P., Bradfield, J. P., Hou, C., Monni, S., Scott, R. H., Asgharzadeh, S., Attiyeh, E. F., Diskin, S. J., Laudenslager, M., Winter, C., Cole, K. A., Glessner, J. T., Kim, C., Frackelton, E. C., Casalunovo, T., Eckert, A. W., Capasso, M., Rappaport, E. F., McConville, C., London, W. B., Seeger, R. C., Rahman, N., Devoto, M., Grant, S. F.A., Li, H., Hakonarson, H.
(2008). Chromosome 6p22 Locus Associated with Clinically Aggressive Neuroblastoma. NEJM
358: 2585-2593
[Abstract][Full Text]
Cole, K. A., Attiyeh, E. F., Mosse, Y. P., Laquaglia, M. J., Diskin, S. J., Brodeur, G. M., Maris, J. M.
(2008). A Functional Screen Identifies miR-34a as a Candidate Neuroblastoma Tumor Suppressor Gene. Mol Cancer Res
6: 735-742
[Abstract][Full Text]
Cascon, A, Landa, I, Lopez-Jimenez, E, Diez-Hernandez, A, Buchta, M, Montero-Conde, C, Leskela, S, Leandro-Garcia, L J, Leton, R, Rodriguez-Antona, C, Eng, C, Neumann, H P H, Robledo, M
(2008). Molecular characterisation of a common SDHB deletion in paraganglioma patients. J. Med. Genet.
45: 233-238
[Abstract][Full Text]
Hero, B., Simon, T., Spitz, R., Ernestus, K., Gnekow, A. K., Scheel-Walter, H.-G., Schwabe, D., Schilling, F. H., Benz-Bohm, G., Berthold, F.
(2008). Localized Infant Neuroblastomas Often Show Spontaneous Regression: Results of the Prospective Trials NB95-S and NB97. JCO
26: 1504-1510
[Abstract][Full Text]
Boller, D., Schramm, A., Doepfner, K. T., Shalaby, T., von Bueren, A. O., Eggert, A., Grotzer, M. A., Arcaro, A.
(2008). Targeting the Phosphoinositide 3-Kinase Isoform p110{delta} Impairs Growth and Survival in Neuroblastoma Cells. Clin. Cancer Res.
14: 1172-1181
[Abstract][Full Text]
Longoni, M., Orzan, F., Stroppi, M., Boari, N., Mortini, P., Riva, P.
(2008). Evaluation of 1p36 markers and clinical outcome in a skull base chordoma study. Neuro Oncology
10: 52-60
[Abstract][Full Text]
Pang, J.-Z., Qin, L.-X., Ren, N., Hei, Z.-Y., Ye, Q.-H., Jia, W.-D., Sun, B.-S., Lin, G.-L., Liu, D.-Y., Liu, Y.-K., Tang, Z.-Y.
(2007). Loss of Heterozygosity at D8S298 Is a Predictor for Long-term Survival of Patients with Tumor-Node-Metastasis Stage I of Hepatocellular Carcinoma. Clin. Cancer Res.
13: 7363-7369
[Abstract][Full Text]
Drew, S.
(2007). `Having cancer changed my life, and changed my life forever': survival, illness legacy and service provision following cancer in childhood. Chronic Illness
3: 278-295
[Abstract]
Ross, C. W., Ouillette, P. D., Saddler, C. M., Shedden, K. A., Malek, S. N.
(2007). Comprehensive Analysis of Copy Number and Allele Status Identifies Multiple Chromosome Defects Underlying Follicular Lymphoma Pathogenesis. Clin. Cancer Res.
13: 4777-4785
[Abstract][Full Text]
Chen, Y., Stallings, R. L.
(2007). Differential Patterns of MicroRNA Expression in Neuroblastoma Are Correlated with Prognosis, Differentiation, and Apoptosis. Cancer Res.
67: 976-983
[Abstract][Full Text]
Oberthuer, A., Berthold, F., Warnat, P., Hero, B., Kahlert, Y., Spitz, R., Ernestus, K., Konig, R., Haas, S., Eils, R., Schwab, M., Brors, B., Westermann, F., Fischer, M.
(2006). Customized Oligonucleotide Microarray Gene Expression-Based Classification of Neuroblastoma Patients Outperforms Current Clinical Risk Stratification. JCO
24: 5070-5078
[Abstract][Full Text]
Asgharzadeh, S., Pique-Regi, R., Sposto, R., Wang, H., Yang, Y., Shimada, H., Matthay, K., Buckley, J., Ortega, A., Seeger, R. C.
(2006). Prognostic Significance of Gene Expression Profiles of Metastatic Neuroblastomas Lacking MYCN Gene Amplification.. JNCI J Natl Cancer Inst
98: 1193-1203
[Abstract][Full Text]
Kobayashi, K., Era, T., Takebe, A., Jakt, L. M., Nishikawa, S.-I.
(2006). ARID3B Induces Malignant Transformation of Mouse Embryonic Fibroblasts and Is Strongly Associated with Malignant Neuroblastoma.. Cancer Res.
66: 8331-8336
[Abstract][Full Text]
Wang, Q., Diskin, S., Rappaport, E., Attiyeh, E., Mosse, Y., Shue, D., Seiser, E., Jagannathan, J., Shusterman, S., Bansal, M., Khazi, D., Winter, C., Okawa, E., Grant, G., Cnaan, A., Zhao, H., Cheung, N.-K., Gerald, W., London, W., Matthay, K. K., Brodeur, G. M., Maris, J. M.
(2006). Integrative genomics identifies distinct molecular classes of neuroblastoma and shows that multiple genes are targeted by regional alterations in DNA copy number.. Cancer Res.
66: 6050-6062
[Abstract][Full Text]
Spitz, R., Hero, B., Simon, T., Berthold, F.
(2006). Loss in Chromosome 11q Identifies Tumors with Increased Risk for Metastatic Relapses in Localized and 4S Neuroblastoma.. Clin. Cancer Res.
12: 3368-3373
[Abstract][Full Text]
Tang, X. X., Zhao, H., Kung, B., Kim, D. Y., Hicks, S. L., Cohn, S. L., Cheung, N.-K., Seeger, R. C., Evans, A. E., Ikegaki, N.
(2006). The MYCN Enigma: Significance of MYCN Expression in Neuroblastoma.. Cancer Res.
66: 2826-2833
[Abstract][Full Text]
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