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[Cancer Research 62, 6481-6484, November 15, 2002]
© 2002 American Association for Cancer Research

Advances in Brief

No Evidence for the Presence of an Imprinted Neuroblastoma Suppressor Gene within Chromosome Sub-Band 1p36.31

Michael D. Hogarty2, Cynthia L. Winter, Xueyuan Liu, Chun Guo, Peter S. White, A. Thomas Look, Garrett M. Brodeur and John M. Maris

Division of Oncology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104-4318 [M. D. H., C. L. W., X. L., C. G., P. S. W., G. M. B., J. M. M.]; Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 [M. D. H., P. S. W., G. M. B., J. M. M.]; and Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115 [A. T. L.]


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 
Deletion of the distal short arm of chromosome 1 occurs in 35% of primary neuroblastomas (NBs). These deletions tend to be large and extend to the telomere, but a common region within sub-band 1p36.3 is consistently lost. Despite intensive investigation, no candidate tumor suppressor gene within this region has been shown to undergo tumor-specific mutation consistent with biallelic inactivation. In addition, initial studies demonstrated preferential loss of the maternally inherited 1p homologue in NBs with 1p loss of heterozygosity (LOH) without MYCN amplification. This has led to the widely accepted hypothesis that a genomically imprinted NB suppressor gene is the target of 1p deletion in this subset. To test this hypothesis we have studied 293 primary NBs for LOH within 1p36.3 and determined the parental origin of the deleted 1p homologue. LOH within 1p36.3 was demonstrated in 55 NBs (19%). Of these, 29 occurred in tumors without MYCN amplification: 13 had deletion of the maternally inherited 1p, whereas 16 had deletion of the paternally inherited 1p (P = 0.58). These data strongly refute a parent-of-origin effect for 1p deletions in NB and exclude the existence of an imprinted NB suppressor locus in this region.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results and Discussion
 REFERENCES
 
Cytogeneticists first identified alterations of the distal short arm of chromosome 1 (1p) in primary NBs and tumor-derived cell lines >20 years ago (1) . Molecular analyses have subsequently confirmed and extended these initial findings with uniform results. Deletions within 1p occur in ~35% of primary NBs, and these deletions tend to be large and terminal, often extending from ~1p32 to the telomere (2, 3, 4) . Interstitial deletions are infrequent, and a SRO3 has been identified consistently within 1p36.3 (5, 6, 7) . Constitutional genomic alterations within this region have also been characterized in patients with NB, and may predispose to the genesis of this tumor (8 , 9) . Finally, transfer of 1p chromosomal material into a NB-derived cell line has induced phenotypic changes consistent with loss of malignant potential and reversion to tumorigenicity correlated with loss of the transferred 1p homologue (10) . Taken together, these data strongly support the presence of one or more NB suppressor genes within chromosome sub-band 1p36.3. However, tumor-specific biallelic inactivation has not been demonstrated for any candidate 1p36 suppressor gene in NB despite intensive investigation. Thus, alternate models of tumor-suppressor inactivation such as genomic imprinting, somatic epigenetic silencing, haploinsufficiency, and dominant inhibitor effect have been postulated. Reports documenting preferential deletion of the maternally inherited 1p in NBs without MYCN amplification led to the hypothesis that an imprinted suppressor gene is targeted for disruption in this subset (11 , 12) . Deletion of the normally expressed homologue (inherited through the maternal genome in this instance) of an imprinted suppressor gene would result in biallelic inactivation because the paternally inherited homologue would be epigenetically silenced. Additional support arose from the observation that 1p deletions in NBs without MYCN amplification tend to be smaller and define a more telomeric SRO than those in NBs with MYCN amplification (12) . These findings have supported speculation that a more telomeric 1p NB suppressor gene that is regulated by genomic imprinting is targeted for disruption in NBs without MYCN amplification, whereas a more proximal nonimprinted suppressor gene is targeted by deletions in MYCN-amplified NBs. To test this hypothesis we have determined the parental origin of the deleted 1p allele in a large series of NBs, both with and without MYCN amplification, and show that no parent-of-origin effect for 1p36 deletion is apparent to support the presence of an imprinted NB suppressor gene in this region.


   Materials and Methods
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 ABSTRACT
 Introduction
 Materials and Methods
Results and Discussion
 REFERENCES
 
Patients and Tissue Samples.
A total of 293 NB cases were ascertained in which tumor tissue, constitutional tissue (blood or bone marrow without tumor infiltration), and blood from one or both parents were available for DNA extraction and PCR amplification. Patients had been registered and tissue specimens banked through the following United States cooperative group biology studies: Pediatric Oncology Group-9047, CCG-B947, and CCG-B974. Eligibility criteria required that tumor samples contain >80% NB cells. Tumor MYCN status was determined by fluorescence in situ hybridization with amplification defined as >=10 MYCN signals within a tumor cell and was performed in the cooperative group reference laboratory as described previously (13) . Tumor histopathology was classified according to the system of Shimada et al. (14) , and stage was assigned using the INSS (15) . DNA was extracted from tumors, blood, and bone marrow samples using Qiagen anion-exchange chromatography (Qiagen Inc., Valencia, CA). All of the patients and/or legal guardians signed informed consent, and this study was approved by the Children’s Hospital of Philadelphia Institutional Review Board.

LOH and Parental Origin of Deleted Allele Determination Studies.
LOH was assessed after PCR amplification of matched tumor/constitutional DNA pairs. Fluorescence-labeled primers for the highly polymorphic markers D1S468, D1S2660, and D1S214 (which map within 1p36.3) were obtained from ABI and used in a triplex PCR reaction to screen for LOH. Briefly, PCR was performed in a 15 µl volume with a final concentration of 1 µM for each of the primers, 1 mM of each deoxynucleoside triphosphate, 2.5 mM MgCl2, 1x GeneAmp PCR Buffer II, 0.6 units AmpliTaq Gold (Perkin-Elmer Applied Biosystems, Branchburg, NJ), and 60 ng of genomic DNA. Amplification was performed in an MJ Research Thermal cycler (Watertown, MA) at the following conditions: 12 min initial denaturation at 95°C; 10 cycles of 94°C x 15 s, 55°C x 15 s, 72°C x 30 s; 20 cycles of 89°C x 15 s, 55°C x 15 s, 72°C x 30 s; and 10 min final extension at 72°C. The reaction products were analyzed by electrophoresis performed on a PE ABI Model 377 DNA sequencer. Data were collected and analyzed with the Genescan and Genotyper software packages (Applied Biosystems, Foster City, CA) that determined allele length, fluorescence signal peak intensity, and area under the curve for each marker used. Patient tumor and blood electropherograms were compared to determine LOH according to the formula: (area normal allele 1/area normal allele 2) ÷ (area tumor allele 1/area tumor allele 2) with LOH defined as a score of <=0.5 or >=2.0 (i.e., >2-fold reduction in intensity for either tumor-derived allele) at two or more informative markers. In cases with a single informative locus, the markers D1S450 and D1S2667 were also tested. Electropherograms demonstrating LOH were repeated and confirmed from an independent PCR reaction. At that time, PCR products amplified from parental DNA were analyzed in parallel. The parental origin of the deleted allele was determined by direct inspection of a minimum of two markers with LOH, and in each case the origin of the deleted homologue was identified without disparity. The {chi}2 test for statistical significance was performed to compare clinical and biological features of tumors with and without 1p LOH, and to determine whether there was preferential deletion of the 1p allele inherited from either parent.


   Results and Discussion
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 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
REFERENCES
 
The patient demographics and tumor-specific biological features for the study group of 293 NB cases are shown in Table 1Citation . The study group reflects an intentional bias toward lower-risk group disease, as our a priori intent was to identify NB cases with 1p deletion in the absence of MYCN amplification. We hypothesized that these tumors would be over-represented in patients without high-risk features. Localized NBs (INSS stages 1, 2, or 3) accounted for 61% of tumors in which staging information was available, whereas in most unbiased series ~40% present as localized masses. A similar skewing toward NBs with favorable biological features is evidenced by only 12% of tumors having amplification of MYCN compared with 20–25% from unselected series and >60% having favorable histopathology.


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  		Table 1 Clinical and biological features of NBs with and without 1p36.3 loss of heterozygosity (n = 293)

 
Of the 293 NBs in the study group, 55 (19%) demonstrated LOH within chromosome sub-band 1p36.3 (Table 1)Citation . As anticipated, the percentage with 1p LOH was lower than the 30–35% observed in unselected series, as 1p allelic loss cosegregates with unfavorable biological features such as amplification of MYCN (16) . Still, NBs with 1p deletion were more likely to have metastasized at diagnosis (71% versus 31%) and to have unfavorable INPC histopathology (74% versus 31%) supporting an association with biologically unfavorable disease (P < 0.001). Of the 35 NBs with MYCN amplification, 26 (74%) demonstrated 1p LOH, reflecting the high proportion of 1p allelic loss occurring in MYCN-amplified NBs as reported previously (2) . However, 29 of the NBs (53%) with 1p LOH identified in our study did not have MYCN amplification (Table 1)Citation . It is this subset that was most relevant to assess for a parent-of-origin effect in 1p allelic loss to test the imprinting hypothesis.

Representative electropherograms from patient blood (normal), NB tissue (tumor), and blood from one or both biological parents are shown in Fig. 1Citation . Determination of the allele inherited from each parent, as well as identification of the parental origin of the deleted 1p homologue in the tumor specimens, was made by direct inspection. In a minority of cases where DNA from only one parent was available, the parental origin of the deleted 1p homologue was unequivocally inferred, as demonstrated in Fig. 1BCitation . In all of the cases where 1p LOH was demonstrated, there was complete concordance for the parental origin of the deleted 1p at multiple loci. For all 55 of the cases there was random loss of 1p homologues (Table 2)Citation , with 25 NBs demonstrating loss of the maternally inherited homologue and 30 demonstrating loss of the paternally inherited homologue (P = 0.50). Of particular interest, the 29 NBs with 1p LOH in the absence of MYCN amplification also demonstrated random loss with 16 of the 29 cases showing loss of the paternally inherited 1p (P = 0.58). These data directly refute a parent-of-origin effect for 1p homologue deletions in NBs with or without MYCN amplification and, therefore, strongly exclude the presence of an imprinted suppressor locus.



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  		Fig. 1. Representative fluorescence electropherograms that depict 1p LOH and the assignment of the parental origin of the deleted 1p allele are shown (analyzed using Genescan and genotyper software packages). A, electropherogram for tumor C-058 at marker D1S2660 [from DNA obtained from blood (normal), NB tissue (tumor), and maternal and paternal blood] demonstrating tumor-specific loss of the paternally inherited 1p allele. Alleles are identified by their length, provided in the first box below each allele tracing, whereas fluorescence signal peak intensity and area under the curve are given in the following two boxes, respectively. B, electropherograms for tumor C-089 at markers D1S468 and D1S2660 showing concordance for 1p LOH and for parental origin of the deleted 1p allele (inferred paternal loss). C, electropherogram for tumor C-083 at marker D1S468 that demonstrates loss of the maternally inherited 1p allele. All NBs scored as having 1p LOH demonstrated LOH at multiple loci and in repeat amplification reactions; all determinations of parental origin of the deleted homologue were concordant at all loci in each case. *, identifies the deleted allele in the tumor sample electropherogram; arrow, identifies the parental allele lost in the NB tissue by direct inspection or extrapolation.

 

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  		Table 2 Parental origin of deleted 1p homologuea in NBs with 1p36.3 deletion

 
Several indirect lines of evidence had suggested previously that a 1p36 NB suppressor gene may be subject to epigenetic silencing through genomic imprinting. First, in an initial study of many NBs, 1p LOH was demonstrated in 24 tumors in the absence of MYCN amplification, and 21 had loss of the maternally inherited 1p homologue (12) . Furthermore, two cases of NB had been reported in children with constitutional deletions within distal 1p36, and in both cases the maternally inherited 1p homologue had been lost (8 , 17) . Taken together, these data reflected an apparent parent-of-origin effect that suggested genomic imprinting may play a role in this region. Second, no homozygous deletions were found in the constitutional cases evaluated, and homozygous deletion was only very rarely detected within 1p36 in NB cell lines (18) . Similarly, no 1p36 candidate gene had been shown to have biallelic inactivation through mutation of the retained homologue, raising consideration that epimutation may be responsible for gene silencing in this region. Finally, in addition to reports of a parent-of-origin effect it had been appreciated that the 1p SRO defined by NBs without MYCN amplification was smaller and more telomeric than the SRO defined by NBs with MYCN amplification. Thus, it has become widely accepted that an imprinted gene within distal 1p36 is targeted for disruption in MYCN single-copy NBs, whereas a more proximal nonimprinted suppressor gene is targeted in MYCN-amplified NBs.

However, we and others have reported smaller series in which the parental origin of 1p homologues was identified in NBs with 1p deletion and single-copy MYCN (19 , 20) . Of four cases, three demonstrated LOH of the paternally inherited 1p, whereas one showed deletion of the maternally inherited homologue. In addition, imprinted genes in mammals tend to cluster within the genome in an arrangement thought to be critical for the maintenance and regulation of epigenetic imprints on functionally related genes (21) . No such cluster of imprinted genes has been mapped to distal 1p. To date, two putative imprinted genes within 1p have been described (22) . ARHI, a RAS homologue, maps within 1p31 far proximal to the NB SRO, and is expressed from the paternally inherited homologue (23) . TP73, a p53 family member, maps within 1p36.3 although telomeric to the NB SRO defined previously (6) . TP73 was initially characterized as a maternally expressed imprinted gene (24) but has been shown to be biallelically expressed in most fetal tissues except brain (25) , and expression has not been shown to be absent or reduced in neuroblastic tumors with hemizygous deletion (26 , 27) .

In our current study we investigated 1p LOH at markers within or closely flanking our previously defined SRO within chromosome sub-band 1p36.3 and did not define the proximal boundaries of these deletions. However, we have investigated previously 566 primary NBs using markers from 1p32 through 1p36 and have identified only one tumor (<0.2%) with a 1p deletion that did not include the 1p36.3 SRO (this tumor deleted 1p32-p34; Ref. 6 ). Other groups have similarly reported a single SRO within distal 1p36 (5 , 7) . Our current findings are consistent with the hypothesis that a single NB suppressor locus is targeted for disruption by deletions within 1p but does not exclude the possibility that loss of function of several contiguous genes within this region is important.

In summary, the distal short arm of chromosome 1 is an intriguing region that has been intensively studied in NB and is deleted frequently in many additional human cancers. Multiple lines of evidence strongly support the presence of a NB suppressor locus within chromosome sub-band 1p36.3, yet to date no bona fide NB suppressor gene(s) has been identified. However, sequencing and annotation of the human genome is rapidly progressing, and many characterized and predicted candidate genes are emerging from analyses of distal 1p. Thus, we have performed this study to unequivocally address the potential role of imprinting in this region, as this has great implications in determining rational testing of these candidate genes as they are identified. Although indirect evidence has supported previously that genomic imprinting of a NB suppressor within 1p36 may contribute to gene inactivation in NBs without MYCN amplification, our data showing no parent-of-origin effects for 1p deletion strongly refute this hypothesis. Our findings do not exclude somatically acquired epigenetic silencing, such as occurs after promoter hypermethylation, nor haploinsufficiency as a mechanism for tumor predisposition after 1p deletion in NB. Similarly, it remains plausible that a tumor suppressor gene within this region will be identified that demonstrates classic biallelic inactivation.


   ACKNOWLEDGMENTS
 
We thank the former CCG and Pediatric Oncology Group for the provision of tumor and tissue specimens, as well as Susan Rowe, Lisa Moreau, and members of the Hogarty, Look, Brodeur, and Maris laboratories for technical support.


   FOOTNOTES
 
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.

1 Supported by NIH Grants RO1CA78745 and U1078966 (to J. M. M.), and by a Career Development Award from the American Society of Clinical Oncology (to M. D. H.), The Richard and Sheila Sanford Chair in Pediatric Oncology, and grant U01-CA30969 (to the Children’s Oncology Group). Back

2 To whom requests for reprints should be addressed, at Children’s Hospital of Philadelphia, Division of Oncology, 9 North ARC, 3615 Civic Center Boulevard, Philadelphia, PA 19104-4318. E-mail: hogartym{at}email.chop.edu Back

3 The abbreviations used are: SRO, smallest region of overlapping deletion; NB, neuroblastoma; INPC, International Neuroblastoma Pathology Committee; INSS, International Neuroblastoma Staging System; LOH, loss of heterozygosity; CCG, Children’s Cancer Group. Back

Received 9/ 3/02. Accepted 9/27/02.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 

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