Biomedical subjects

J M Maris

Publications and source records attributed to J M Maris.

At least 19 recordsLinked to original sources

PubMed2005

Evidence for an age cutoff greater than 365 days for neuroblastoma risk group stratification in the Children's Oncology Group.

PURPOSE: In the Children's Oncology Group, risk group assignment for neuroblastoma is critical for therapeutic decisions, and patients are stratified by International Neuroblastoma Staging System stage, MYCN status, ploidy, Shimada histopathology, and diagnosis age. Age less than 365 days has been associated with favorable outcome, but recent studies suggest that older age cutoff may improve prognostic precision. METHODS: To identify the optimal age cutoff, we retrospectively analyzed data from the Pediatric Oncology Group biology study 9047 and Children's Cancer Group studies 321p1-p4, 3881, 3891, and B973 on 3,666 patients (1986 to 2001) with documented ages and follow-up data. Twenty-seven separate analyses, one for each different age cutoff (adjusting for MYCN and stage), tested age influence on outcome. The cutoff that maximized outcome difference between younger and older patients was selected. RESULTS: Thirty-seven percent of patients were younger than 365 days, and 64% were > or = 365 days old (4-year event-free survival [EFS] rate +/- SE: 83% +/- 1% [n = 1,339] and 45% +/- 1% [n = 2,327], respectively; P < .0001). Graphical analyses revealed the continuous nature of the prognostic contribution of age to outcome. The optimal 460-day cutoff we selected maximized the outcome difference between younger and older patients. Forty-three percent were younger than 460 days, and 57% were > or = 460 days old (4-year EFS rate +/- SE: 82% +/- 1% [n = 1,589] and 42% +/- 1% [n = 2,077], respectively; P < .0001). Using a 460-day cutoff (assuming stage 4, MYCN-amplified patients remain high-risk), 5% of patients (365 to 460 days: 4-year EFS 92% +/- 3%; n = 135) fell into a lower risk group. CONCLUSION: The prognostic contribution of age to outcome is continuous in nature. Within clinically relevant risk stratification, statistical support exists for an age cutoff of 460 days.

Age Factors↗

PubMed2001

Homozygous deletion of CDKN2A (p16INK4a/p14ARF) but not within 1p36 or at other tumor suppressor loci in neuroblastoma.

Loss of heterozygosity of several specific genomic regions is frequently observed in neuroblastoma tumors and cell lines, but homozygous deletion (HD) is rare, and no neuroblastoma tumor suppressor gene (TSG) has yet been identified. We performed a systematic search for HD, indicative of a disrupted TSG, in a panel of 46 neuroblastoma cell lines. An initial search focused on a well-characterized consensus region of hemizygous deletion at 1p36.3, which occurs in 35% of primary neuroblastomas. Each cell line was screened with 162 1p36 markers, for a resolution of 13 kb within the consensus 1p36.3 deletion region and 350 kb throughout the remainder of 1p36. No HDs were detected. This approach was expanded to survey 21 known TSGs, specifically targeting intragenic regions frequently inactivated in other malignancies. HD was detected only at the CDKN2A (p16INK4a/p14ARF) gene at 9p21 and was observed in 4 of 46 cell lines. The observed region of HD included all exons of both CDKN2A and the closely linked CDKN2B (p15INK4b) gene for cell lines LA-N-6 and CHLA-174, all exons of CDKN2A but none of CDKN2B for CHLA-179, and only 104 bp within CDKN2A exon 2 for CHLA-101. All four deletions are predicted to inactivate the coding regions of both p16INK4a and p14ARF. HD was observed in corresponding primary tumor samples for CHLA-101 and CHLA-174 but was not present in constitutional samples. These results suggest that for neuroblastoma, large HDs do not occur within 1p36, most known TSGs are not homozygously deleted, and biallelic inactivation of CDKN2A may contribute to tumorigenicity in a subset of cases.

Blotting, Southern↗

PubMed2001

Biological aspects of neuroblastomas identified by mass screening in Quebec.

BACKGROUND: Neuroblastoma has several characteristics that suggest that preclinical diagnosis might improve outcome. Therefore, the Quebec Neuroblastoma Screening Project was undertaken from 1989 to 1994 to examine infants at 3 weeks and 6 months by measuring urinary catecholamine metabolites. PROCEDURE: Over the 5-yr period, 45 tumors were detected by screening, 20 were identified clinically prior to the third week, and 64 were identified clinically at a later time. We analyzed available tumors for Shimada histopathology, tumor ploidy, MYCN copy number and serum ferritin. RESULTS: Of the tumors detected by screening, only 2 of 45 tested had unfavorable histology, 2 of 45 had diploid or tetraploid DNA content, 0 of 43 had MYCN amplification, and 4 of 44 had elevated serum ferritin. All of these patients are alive and well. The 20 patients detected prior to the 3-week screen had similar biological characteristics. In contrast, of the patients detected clinically after 3 weeks of age, 19 of 51 testedhad unfavorable histology, 25 of 66 had diploid or tetraploid tumors, 12 of 56 had MYCN amplification, and 14 of 54 had elevated ferritin. CONCLUSIONS: The difference between the screened and clinically detected cases was highly significant for each biological variable. Preliminary data on other biological variables, such as neurotrophin expression and allelic loss on 1 p in these patients are consistent with the above findings. These data suggest that mass screening for neuroblastoma at or before 6 months of age detects almost exclusively tumors that have favorable biological characteristics, many of which might have regressed spontaneously. Thus, continued mass screening for neuroblastoma at 6 months is unlikely to accomplish its intended goal, and should probably be discontinued.

Age Factors↗

PubMed2001

Allelic deletion at chromosome bands 11q14-23 is common in neuroblastoma.

BACKGROUND: Neuroblastoma tumorigenesis may involve the differential inactivation of multiple tumor suppressor genes. Recent data have suggested that a neuroblastoma suppressor gene may be located on the long arm of chromosome 11 (11q). PROCEDURE: We therefore analyzed 295 primary neuroblastomas from a representative group of patients for loss of heterozygosity (LOH) at 25 polymorphic markers spanning 11q. RESULTS: LOH was observed in 129 primary neuroblastomas (44%), and a common region of LOH mapped to 11q14-23. No correlation was found between 11q LOH and adverse prognostic variables, but a strong inverse relationship between 11q LOH and MYCN amplification (P < 0.001) was observed. There was no difference in overall survival when patients were stratified by 11q LOH status. However, 11q LOH was associated with a decreased overall survival probability when patients whose tumors had a single copy of MYCN were analyzed separately (P = 0.008). CONCLUSION: These data support the hypothesis that a tumor suppressor gene mapping within 11q14-23 is frequently inactivated during the malignant evolution of neuroblastoma.

Alleles↗

PubMed2001

Loss of heterozygosity for chromosome 14q in neuroblastoma.

BACKGROUND: Neuroblastoma is a genetically heterogeneous disease, with subsets of tumors demonstrating rearrangements of several genomic regions. Preliminary studies from several groups have identified loss of heterozygosity (LOH) for the long arm of chromosome 14 (14q) in 20-25% of primary neuroblastomas. PROCEDURE: To determine precisely the frequency and extent of 14q deletions, we performed LOH analysis for a large series of primary neuroblastomas using a panel of 11 highly polymorphic markers. RESULTS: LOH was detected in 83 of 372 tumors (22%). Although the majority of tumors with allelic loss demonstrated allelic loss for all informative markers, 13 cases showed LOH for only a portion of 14q. A single consensus region of deletion, which was shared by all tumors with 14q LOH, was defined within 14q23-q32 between D14S588 and the 14q telomere. Allelic loss for 14q was strongly correlated with the presence of 11q LOH (P < 0.001 ) and inversely correlated with MYCN amplification (P= 0.04). CONCLUSIONS: LOH for 14q was evident in all clinical risk groups, indicating that this abnormality may be a universal feature of neuroblastoma tumor development. These findings suggest that a tumor suppressor gene involved in the initiation or progression of neuroblastoma is located within distal 14q.

Child↗

PubMed2001

Comprehensive analysis of chromosome 1p deletions in neuroblastoma.

BACKGROUND: Chromosome 1p deletions are common in advanced neuroblastomas, but the biological and clinical implications of this clonal rearrangement remain controversial. Previous studies of chromosome 1p loss of heterozygosity (LOH) have been limited by analyses of relatively small number of tumors derived from heterogeneously assessed and treated patient populations. Therefore, a strictly representative cohort of 288 Children's Cancer Group neuroblastoma patients treated on the most recent phase III therapeutic trials was identified. PROCEDURE: Primary tumors from these patients were analyzed for LOH at precisely mapped and highly informative 1p polymorphic loci located from 1p32 to 1p36.3 by multiplex PCR. RESULTS: Ninety-three primary tumor specimens (32%) had LOH at multiple 1p36 marker loci. All 1p deletions overlapped the previously determined smallest region of overlap (SRO). One tumor had a small terminal deletion completely within 1p36.3, allowing for further refinement of the 1p36 SRO. We found no evidence to support an additional, nonoverlapping region of LOH within 1p32-36. We confirmed the strong correlation of 1p36 LOH with MYCN amplification (P < 0.001), advanced disease stage (P < 0.001), and decreased both 3-year event-free survival and overall survival probabilities (P< 0.001). When stratified for MYCN amplification status or entered into a multivariate analysis, 1p36 LOH remained predictive for decreased event-free survival, but not overall survival probability. CONCLUSIONS: These data support the hypothesis that inactivation of a tumor suppressor gene within 1p36.3 is associated with an increased risk for disease relapse.

Alleles↗

PubMed2001

Detailed molecular analysis of 1p36 in neuroblastoma.

BACKGROUND: Several lines of evidence es tablish that chromosome band 1p36 is frequently deleted in neuroblastoma primary tumors and cell lines, suggesting that a tumor suppressor gene within this region is involved in the development of this tumor. PROCEDURE: We analyzed the status of 1p36 in primary neuroblastomas and cell lines to define the region of consistent rearrangement. RESULTS: Loss of heterozygosity (LOH) studies of primary neuro blastomas identified allelic loss in 135 of 503 tumors (27%), with the smallest region of overlap (SRO) defined distal to D15214 (1p36.3). No homozygous deletions were detected at 120 loci mapping to 1p36.1-p36.3 in a panel of 46 neuroblastoma cell lines. A recently identified patient with neuroblastoma was found to have a constitutional deletion within 1p36.2-p36.3, and this deletion, when combined with the LOH results, defined a smaller SRO of one megabase within 1p36.3. We constructed a comprehensive integrated map of chromosome 1 containing 11,000 markers and large-insert clones, a high-resolution radiation hybrid (RH) map of 1p36, and a P1-artificial chromosome (PAC) contig spanning the SRO, to further characterize the region of interest. Over 768 kb (75%) of the SRO has been sequenced to completion. Further analysis of distal 1p identified 113 transcripts localizing to 1p36, 21 of which were mapped within the SRO. CONCLUSION: This analysis will identify suitable positional candidate transcripts for mutational screening and subsequent identification of the 1p36.3 neuroblastoma suppressor gene.

Alleles↗

PubMed2001

Analysis of genomic imprinting at 1p35-36 in neuroblastoma.

BACKGROUND: Deletion of the distal short arm of chromosome 1 occurs in 25-35% of primary neuroblastomas, and a putative tumor suppressor gene has been mapped to a consensus region of deletion at 1p36.2-36.3. Indirect evidence suggests the presence of an imprinted neuroblastoma suppressor gene within this region, as well as an additional nonimprinted, proximal suppressor gene, inactivation of which correlates with MYCN amplification. PROCEDURE: To test this hypothesis, we performed 1p loss of heterozygosity (LOH) studies on a series of neuroblastomas for which parental DNA had been collected. PCR-formatted polymorphic markers were used to determine the size of the 1p deletion and the parental origin of the deleted 1p homologue. RESULTS: Twenty-six neuroblastomas with 1p LOH were evaluated. Twenty-four had MYCN amplification, and of these, 15 demonstrated loss of the paternally inherited 1p. Two neuroblastomas with a single copy of MYCN were evaluated and both had deletion of the paternally inherited 1p, with one case exhibiting a small terminal deletion. In addition, we have reviewed 49 previously reported neuroblastomas where 1p LOH data and the parental origin of the deleted lp homologue were available. CONCLUSIONS: Analyzed together, these 75 neuroblastomas demonstrate random deletion of parental 1p homologues (P = 0.30). Further, tumors with smaller deletions (breakpoints distal to D1S201 or D1S7) showed a random loss of the parental 1p homologues (P = 0.59), contrary to the expected preferential maternal 1p deletion if an imprinted suppressor gene mapped to this region. However, 19 tumors with 1p LOH and single copy MYCN had deletion of the maternal 1p homologue preferentially (P = 0.02), which does not exclude the possibility that loss of an imprinted suppressor gene plays a role in this subset.

Adult↗

PubMed2001

The angiogenesis inhibitor tnp-470 effectively inhibits human neuroblastoma xenograft growth, especially in the setting of subclinical disease.

Tumor vascularity is highly correlated with disease outcome in neuroblastoma. Thus, novel therapeutics that target the vascular endothelium are candidates for incorporation into clinical trials. We therefore examined the effect of TNP-470 on human neuroblastoma growth in mouse models reflecting both clinically evident and minimal disease. Mice were inoculated s.c. or by tail vein injection with 10(7) human neuroblastoma-derived CHP-134 cells and treated with TNP-470 (100 mg/kg/dose s.c. three times a week or by continuous infusion) or saline. Treatment was given as a single agent in established xenografts, 10 days after 450 mg/kg of cyclophosphamide, or 12 h after tumor inoculation. Tumor growth rate was markedly inhibited in mice receiving TNP-470 administered alone both s.c. and by continuous infusion with a treatment to control ratio (T:C) at day 16 of 0.3 (P < 0.001) and a T:C at day 30 of 0.4 (P = 0.029) for each dosing method, respectively. TNP-470 also significantly inhibited tumor growth when administered following cyclophosphamide (T:C at day 30 = 0.2, P < 0.001) and inhibited disease establishment when given shortly after xenograft inoculation (T:C at day 30 = 0.1, P < 0.001) or tail vein injection. TNP-470 was shown to directly inhibit angiogenesis by Matrigel assay (P =.010) and to increase the apoptotic index in treated tumors. These data show that TNP-470 is a potent inhibitor of human neuroblastoma growth rate and tumorigenicity. We speculate that TNP-470 may be a useful adjuvant therapy for high-risk neuroblastoma patients, particularly when used in settings of minimal disease status.

Angiogenesis Inhibitors↗

PubMed2000

A novel human processed gene, DAD-R, maps to 12p12 and is expressed in several organs.

A cDNA of a processed gene of human DAD-1 (defender against apoptotic cell death) was cloned from the human neuroblastoma cell line SH-SY5Y. The genomic sequence of this novel processed gene, DAD-R, lacked introns and was flanked by 8 bp terminal repeats. RT-PCR showed that the transcript is expressed predominantly in testis, ovaries, pancreas, lung and skeletal muscle. DAD-R has several possible initiation codons, one of them producing an open reading frame comprising 75% of the DAD-1 gene. We determined the chromosomal localization of DAD-R as 12p11.2-12p12.1, an area linked to familial synpolydactyly and frequently amplified in a variety of cancers, including those of testis, ovaries, pancreas and lungs.

Amino Acid Sequence↗

PubMed2000

Identification of a 1-megabase consensus region of deletion at 1p36.3 in primary neuroblastomas.

BACKGROUND: Deletion of the distal short arm of chromosome 1 occurs frequently in neuroblastoma. In addition, neuroblastoma has been described in children with constitutional deletions within 1p36, supporting the existence of one or more neuroblastoma suppressor genes within this region. PROCEDURE: We have pursued a 1p36 tumor suppressor gene identification strategy that has included deletion mapping of 566 primary neuroblastomas and 46 neuroblastoma-derived cell lines, and have determined the parental origin of the deleted 1p homologue in 44 cases to determine whether there is evidence for genomic imprinting within this region. RESULTS AND CONCLUSIONS: We have identified a 1-Mb consensus region of deletion within 1p36.3 defined by primary tumor deletions, constructed a physical map of the region that is being sequenced to completion, and have identified and prioritized candidate genes within this region for further analyses.

Alleles↗

PubMed2000

Localization of a hereditary neuroblastoma predisposition gene to 16p12-p13.

BACKGROUND: Hereditary predisposition to develop neuroblastoma segregates as an autosomal dominant Mendelian trait. PROCEDURE: We have performed linkage analysis on 10 families with neuroblastoma to localize a hereditary neuroblastoma predisposition gene (HNB1). RESULTS: A single genomic interval at chromosome bands 16p12-p13 was consistent with linkage (lod = 3.46), and identification of informative recombinants defined a 25.9-cM critical region between D16S748 and D16S3068. Loss of heterozygosity was identified in 5/12 familial (42%) and 55/259 nonfamilial (21%) neuroblastomas at multiple 16p polymorphic loci. A 12.8-cM smallest region of overlap of deletions was identified within the interval defined by linkage analysis (tel-D16S764-D16S412-cen). CONCLUSIONS: Taken together, these data suggest that HNB1 is located at 16p12-p13 and that inactivation of this gene may contribute to the pathogenesis of nonfamilial neuroblastomas.

Child↗

PubMed2000

Deletion of 11q23 is a frequent event in the evolution of MYCN single-copy high-risk neuroblastomas.

BACKGROUND: Deletions of the long arm of chromosome 11 are frequently identified in human neuroblastomas. PROCEDURE: We screened 394 primary neuroblastomas and 52 tumor-derived cell lines with a panel of 11q and 11p polymorphic markers to determine the frequency of chromosome 11 allelic deletion, and to differentiate partial deletions of chromosome 11q (unb[11q] LOH) from whole chromosome loss. RESULTS: Allelic deletion occurred most frequently at cytogenetic band 11q23 and was detected in 161 primary neuroblastomas (41%) and 18 cell lines (35%). Eighty-seven tumors (22%) had unb[11q] LOH with a heterogeneous distribution of deletion breakpoints. Unb[11q] LOH was highly correlated with age > 1 year at diagnosis (P = 0.008), stage 4 disease (P = 0.001), unfavorable Shimada histopathology (P < 0.001), and assignment to a high-risk therapeutic protocol (P < 0.001), and was inversely correlated with MYCN amplification (P = 0.018). Patients whose tumors showed unb[11q] LOH were less likely to survive (P < 0.001), but there was only a trend towards an independent prognostic influence in multivariate analyses. CONCLUSIONS: Thus, structural rearrangements resulting in unb[11q] LOH commonly occur during the malignant evolution of high-risk neuroblastomas with single-copy MYCN.

Alleles↗

PubMed2000

BIN1 inhibits colony formation and induces apoptosis in neuroblastoma cell lines with MYCN amplification.

BACKGROUND: MYCN amplification and overexpression occurs in 25% of neuroblastomas and independently predicts for poor prognosis disease, an effect thought to be mediated by its role as a transcriptional activator of growth promoting genes. However, in many mammalian cells, deregulated expression of MYC family genes (including MYCN) induces apoptosis. We hypothesized that BIN1, a MYC interacting protein capable of inducing apoptosis, may be an important regulator of MYCN in neuroblastoma. RESULTS: BIN1 expression was found to be reduced in MYCN-amplified cell lines. Further, forced expression of BIN1 markedly reduced colony formation in MYCN-amplified, but not single-copy, cell lines. This effect appeared to be caused by an increase in apoptosis, and was augmented by serum deprivation and concurrent cytotoxic drug therapy in cell culture CONCLUSION: BIN1 inactivation may be necessary for MYCN overexpression to lead to cellular proliferation rather than programmed cell death in neuroblastomas with MYCN amplification.

Adaptor Proteins, Signal Transducing↗

PubMed2000

Inhibition of tumor growth in a human neuroblastoma xenograft model with TNP-470.

UNLABELLED: Background and Procedure High-risk neuroblastoma disease features are correlated with tumor vascularity, suggesting that angiogenesis inhibitors may be a useful addition to current therapeutic strategies. We therefore examined the efficacy of TNP-470 (TAP Pharmaceuticals, Deerfield, IL) in human neuroblastoma xenograft models. RESULTS: Tumor growth rate was markedly inhibited in mice receiving TNP-470 administered alone with a treatment to control ratio (T/C) at day 21 = 0.4 (P <.001). TNP-470 also significantly inhibited tumorigenicity when administered shortly after xenograft inoculation (T/C at day 30 = 0.1, P <.001) and when administered following cyclophosphamide (T/C at day 35 = 0.1, P <.001). CONCLUSIONS: These data show that TNP-470 is a potent inhibitor of human neuroblastoma growth both alone and when given with conventional chemotherapy, suggesting that it may be a useful adjunctive therapy for high-risk neuroblastoma patients.

Angiogenesis Inhibitors↗

PubMed2000

Familial dyserythropoietic anaemia and thrombocytopenia due to an inherited mutation in GATA1.

Haematopoietic development is regulated by nuclear protein complexes that coordinate lineage-specific patterns of gene expression. Targeted mutagenesis in embryonic stem cells and mice has revealed roles for the X-linked gene Gata1 in erythrocyte and megakaryocyte differentiation. GATA-1 is the founding member of a family of DNA-binding proteins that recognize the motif WGATAR through a conserved multifunctional domain consisting of two C4-type zinc fingers. Here we describe a family with X-linked dyserythropoietic anaemia and thrombocytopenia due to a substitution of methionine for valine at amino acid 205 of GATA-1. This highly conserved valine is necessary for interaction of the amino-terminal zinc finger of GATA-1 with its essential cofactor, FOG-1 (for friend of GATA-1; refs 9-12). We show that the V205M mutation abrogates the interaction between Gata-1 and Fog-1, inhibiting the ability of Gata-1 to rescue erythroid differentiation in an erythroid cell line deficient for Gata-1 (G1E). Our findings underscore the importance of FOG-1:Gata-1 associations in both megakaryocyte and erythroid development, and suggest that other X-linked anaemias or thrombocytopenias may be caused by defects in GATA1.

Adult↗

PubMed2000

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.

PURPOSE: To determine the independent prognostic significance of 1p36 loss of heterozygosity (LOH) in a representative group of neuroblastoma patients. PATIENTS AND METHODS: Diagnostic tumor specimens from 238 patients registered onto the most recent Children's Cancer Group phase III clinical trials were assayed for LOH with 13 microsatellite polymorphic markers spanning chromosome band 1p36. Allelic status at 1p36 was correlated with other prognostic variables and disease outcome. RESULTS: LOH at 1p36 was detected in 83 (35%) of 238 neuroblastomas. There was a correlation of 1p36 LOH with age at diagnosis greater than 1 year (P = .026), metastatic disease (P<.001), elevated serum ferritin level (P<.001), unfavorable histopathology (P<.001), and MYCN oncogene amplification (P<.001). LOH at 1p36 was associated with decreased event-free survival (EFS) and overall survival (OS) probabilities (P<.0001). For the 180 cases with single-copy MYCN, 1p36 LOH status was highly correlated with decreased EFS (P = .0002) but not OS (P = .1212). Entering 1p36 LOH into a multivariate regression model suggested a trend toward an independent association with decreased EFS (P = .0558) but not with decreased OS (P = .3687). Furthermore, allelic status at 1p36 was the only prognostic variable that was significantly associated with decreased EFS in low-risk neuroblastoma patients (P = .0148). CONCLUSION: LOH at 1p36 is independently associated with decreased EFS, but not OS, in neuroblastoma patients. Determination of 1p36 allelic status may be useful for predicting which neuroblastoma patients with otherwise favorable clinical and biologic features are more likely to have disease progression.

Child↗

PubMed1999

Allelic deletion at 11q23 is common in MYCN single copy neuroblastomas.

Deletions of the long arm of chromosome 11 (11q) have been noted in primary neuroblastomas, but a comprehensive analysis has not been performed. Therefore, we analysed 331 neuroblastomas (295 sporadic, 15 familial and 21 tumor-derived cell lines) to determine the prevalence of 11q allelic deletions, to map the location of a putative tumor suppressor gene and to perform clinical correlative studies. Assays for loss of heterozygosity (LOH) were performed at 24 microsatellite loci spanning 11q. LOH was observed at multiple 11q loci in 129/295 (44%) sporadic neuroblastomas, 5/15 (33%) familial neuroblastomas, and 5/21 (24%) neuroblastoma cell lines. A single region of 2.1 cM within 11q23.3, flanked by markers D11S1340 and D11S1299, was deleted in all specimens with 11q LOH. Allelic loss at 11q23 was inversely related to MYCN amplification (P<0.001). Within the subset of cases with a single copy of MYCN, 11q LOH was associated with advanced stage disease (P=0.008), unfavorable histopathology (P=0.042), and decreased overall survival probability (P=0.008). However, 11q LOH was not independently prognostic in multivariate analyses. These data support the hypothesis that a tumor suppressor gene mapping within 11q23.3 is commonly inactivated during the malignant evolution of a large subset of neuroblastomas, especially those with unamplified MYCN.

Alleles↗