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[Cancer Research 62, 1761-1767, March 15, 2002]
© 2002 American Association for Cancer Research

Molecular Biology and Genetics

Novel Regions of Allelic Imbalance Identified by Genome-wide Analysis of Neuroblastoma1

Jaume Mora2, Nai-Kong V. Cheung, Sandra Oplanich, Lishi Chen and William L. Gerald

Departments of Pathology [J. M., S. O., L. C., W. G.] and Pediatrics [N-K. V. C.), Memorial Sloan-Kettering Cancer Center, New York, New York 10021


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Several nonrandom chromosomal abnormalities have been associated withneuroblastoma (NB). However, the relationship of each genetic event to the clinical course of disease is not firmly established. We have performed a genome-wide allelic scan of NB to identify regions with frequent allelic imbalance (AI) and correlate the allelotype with clinical features of disease. Nineteen tumors from patients across the spectrum of NB were used. Genome-wide allelotype was performed using 169 fluorescently labeled microsatellite markers from the Weber 9a human screening set (Research Genetics, Huntsville, AL) and 48 independent markers for high-density analysis of selected regions. Eleven chromosomal regions had AI in >25% of tumors including loci known previously to be frequently altered such as 1p36 (10 of 19; 52%), 2p (9 of 19; 47%), 17q (8 of 19; 42%), 11q23 (8 of 19; 42%), 14q32 (7 of 19; 37%), 19q (6 of 19; 31%), 7q (6 of 19; 31%), 9p21 (5 of 19; 26%), and three novel regions of frequent AI at 10p11-p15 (7 of 19; 40%), 12q24.1 (5 of 19; 26%), and 8qcen–q24 (5 of 19; 26%). AI of four regions (8q, 10p, 19q, and 12q) allowed the distinction of two genetic groups that matched clinical significant subgroups of NB. AI at 12q24 and 19q13 was found exclusively in high-risk local-regional tumors, whereas AI at 10p11 and 8q appeared to be specific for stage 4 tumors with MCYN amplification. Spontaneously remitting or quiescent tumors were intact at all of the regions described above.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In the early 1980s, the first karyotypic reports of NB3 cell lines and stage 4 tumors revealed several nonrandom chromosomal abnormalities associated with the disease including losses on chromosomes 1p and 11q, gains on chromosomes 17q and 1q, the presence of homozygous staining regions and double minutes, and changes in the normal diploid chromosomal content (1, 2, 3, 4, 5) . Amplification of the proto-oncogene MYCN was subsequently identified in the homozygous staining regions and double minutes (6) . In the 1990s, PCR-based LOH and FISH analyses showed alteration of subchromosomal regions not identified previously by karyotyping including losses at 3p, 4p, 9p, and 14q and gains at 5q and 18q in 20–40% of NB tumors of all risk categories (7, 8, 9, 10, 11, 12, 13) . CGH has been used to provide an entire genome survey of NB (14, 15, 16) . These studies confirmed previous data and CGH with multicolor FISH has been used to characterize the multiple chromosomal alterations in NB cell lines (17) . Despite the identification of numerous chromosomal regions that are consistently altered in NB, MYCN is the only gene corresponding to these regions identified to date.

Several regions in NB (such as 1p36) have received detailed PCR-based allelic analysis; however, there has not been a comprehensive, high density, genome-wide allelic study. Only the series of Takita et al. (18) analyzed all chromosomes. This study used 35 RFLP probes and eight microsatellite markers, with only one or two probes for most of the chromosomes.

To provide a comprehensive analysis of AI in NB, we performed a genome-wide scan using 217 fluorescently labeled microsatellite markers with two aims: (a) to identify new areas of AI; and (b) to correlate allelotype patterns with clinical subtypes of NB.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Nineteen frozen tumor specimens each with >75% tumor cell content obtained from 10 patients with stage 4 NB [according to the INSS (19) ], 8 patients with LR NB (INSS stages 1, 2, and 3) and one patient with INSS stage 4s disease were studied. Human tissues were used for biological studies according to the guidelines of the institutional review board.

Clinical and biological characteristics for all cases are summarized in Table 1Citation . High-risk LR NB is defined as disease locally progressing and requiring cytotoxic therapy or progression to stage 4. High-risk stage 4 NB is defined by MYCN amplification.


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  		Table 1 Clinical and biological characteristics for all patients studied

 
Genome-wide allelotyping was performed using the Weber 9a panel of 169 polymorphic microsatellite markers (Research Genetics, Huntsville, AL) evenly distributed with an average of 20-cM genetic distance. The 169 markers were combined into 21 panels containing six to nine markers each of different sizes and dyes (6-carboxyfluorescein, hexachlorafluorescein, tetrachlorafluorescein). The products for each panel were pooled and loaded into a 48-tube tray with 6-carboxytetramethylrhodamine size standard. One run of the 48-tube tray (24 h) is therefore sufficient to analyze each pair sample of tumor and normal DNA for all 169 markers. Alleles were measured using an ABI model 310 automated fluorescent DNA sequencer/genotyper (Applied Biosystems, Foster City, CA). Data were analyzed with GeneScan v3.1 and Genotyper v3.6 NT software (Applied Biosystems, Foster City, CA). Each allele assignment was also confirmed manually. Forty-eight additional markers for region-specific analyses of chromosomes 1p36, 1p22, 11q23, 14q32, 9p21, 17q, and 19q13 were obtained from the genome database (www.gdb.org) and used as published previously (20, 21, 22) .

In comparison to CGH or FISH analyses, use of fluorescent DNA primers for quantitation of PCR products does not readily distinguish gain from loss (23) . The term AI is used, but in some cases previous karyotypic, FISH, or CGH data are available to determine whether it represents gain or loss. AI was determined by comparison of the allelic ratio between the normal and tumor specimen in heterozygous samples as described previously (24) . AI was defined as ratios >1.5 for loss of the shortest allele or <0.5 for the largest in cases of diploid tumor content. For near-triploid tumors, ratios of <0.35 and >2 were used to match the AI criteria for diploid tumors (20) . This formula establishes AI as a >50% reduction in allele intensity and accounts for preferential amplification of the shortest allele (25) .


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Regions of Frequent AI among the Samples Studied
One hundred sixty-nine fluorescent polymorphic markers were used spanning the entire human genome with an average intermarker distance of 20 cM. Information on 48 additional polymorphic markers spanning known regions of AI for NB (1p36, 9p21, 11q23, 14q32, 17q, and 19q13) was available for all of the cases (20, 21, 22) . Fig. 1Citation shows representative electropherogram output data from the ABI 310 Genotyper Software. Multiple microsatellite markers are pooled, and fluorescent intensity for each allele in both nonneoplastic (top panel) and tumor (bottom panel) tissue are analyzed automatically by the sequencer.



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  		Fig. 1. Electropherogram output data from the Genotyper software. Panel 11 from normal (top) and tumor (bottom) pair are shown. Each allele peak is automatically labeled with map-pair number in the panel, bp size, and peak height. The table details the calculations originated from the genotyper software. Category, microsatellite marker; Mker, marker of each panel; Pk1, peak 1 or allele one bp size; Ht1, height off the first peak or allele; Pk2, peak 2 or allele two bp size; Ht2, height off the second peak or allele; PkHtRatio, ratio between allele 2 versus allele 1 heights for each sample; T/NRatio, ratio between PkHt from the normal versus the tumor; Assess, assessment according to predetermined cutoffs.

 
Fig. 2Citation graphs the frequency of AI across all markers for each chromosomal arm with common AI of contiguous markers. The plot demonstrates that most (81%) have regions of <25% AI detected. We therefore chose to focus on regions with >25% AI frequency as representative of commonly altered alleles in NB. Eleven regions, defined as contiguous AI over several markers (see Fig. 2Citation ) with >25% frequency of AI were detected. These included regions of LOH characterized previously on chromosome arms 1p36, 17q, 11q23, 14q32, 19q13, and 9p21 and regions known to be altered by gains in NB such as 2p and 7q (2 , 15 , 16) . The 2p region most likely represents gain of genetic material at the MYCN locus. Overall, the AI frequency for these known regions across all of the samples using the 217 markers set was: 1p36 LOH, 52% (10 of 19); 2p gain, 47% (9 of 19); 17q arm gain, 42% (8 of 19); 11q23 LOH, 42% (8 of 19); 14q32 LOH, 37% (7 of 19); 19q LOH, 31% (6 of 19); 7q gain, 31% (6 of 19); and 9p21 LOH, 26% (5 of 19).



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  		Fig. 2. Frequency plot of AI for all of the consistent hot spots on each chromosomal arms defined across the samples studied. The frequency of altered hot spot regions found in the study are graphed and colored in the chromosomal arms encountered.

 
Three previously unrecognized regions of significant AI were identified at 10p11–p15 (40%; 6 of 15), 12q24.1 (26%; 5 of 19), and 8qcen–q24 (26%; 5 of 19). Fig. 3Citation shows the results of the 11 chromosomal regions with >25% AI for all cases and details the markers defining the minimal areas of AI.



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  		Fig. 3. Summary results for all cases of the 11 chromosomal regions (chromosome column on the left indicates chromosome number) with >25% AI. The microsatellite markers are listed on the left in order from p telomere to q telomere for each chromosome. Cases are listed horizontally as tumor numbers. The markers defining the minimal areas of AI [shortest regions of overlap (SRO) or hot spots for each chromosome are labeled on the right-hand side of each chromosome list with a *]. Green (or +), intact; gray (or 1), homozygote; red (or -), AI. Cases are grouped in three clinically relevant groups of NB: group 1 (left), characterized by their general low frequency of AI and more specifically by intact regions defining groups 2 and 3. Clinically, this group is composed of young patients (all infants except one diagnosed at 13 months of age) with spontaneously remitting or quiescent tumors; group 2 (center), AI at 12q24 and/or 19q13 LOH and intact at chromosomal arm 8qcen–q24, a marker with high frequency of AI in group 3 tumors. Clinically, this group presented as LR disease, with refractory primary tumors despite multimodality therapy; group 3 (right), AI at 8qcen–q24 or 10p11-p15 or both and intact at 19q13 and 12q24.1 regions frequently altered in group 2. Clinically, this group is composed primarily of cases with stage 4 disease at diagnosis and MYCN amplification.

 
Three Distinct Genetic Profiles Distinguish Clinically Relevant Subgroups of NB
The profile of AI for four chromosomal regions (8q, 10p, 19q, and 12q) allowed the distinction of three genetic groups (Tables 1Citation and 2Citation and Fig. 3Citation ). After review of the clinical characteristics and outcome for all cases in each genetic group, distinguishable clinical patterns appeared to correlate with these three genetic profiles (see below). Table 2Citation shows the status of regions with frequent (>25%) AI for the three groups. Color codes highlight the genetic characteristics of each group.


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  		Table 2 Summary of the allelotype pattern for each of the 11 chromosomal arms showing significant (>25%) AI

 
Group 1.
These tumors were characterized genetically by a generally low frequency of AI and more specifically by retained heterozygosity in regions of LOH defining groups 2 and 3 (see Table 2Citation and Fig. 3Citation ). The patients were all very young (all presented at <13 months of age) with spontaneously remitting or quiescent tumors. One patient with an INSS stage 4s diploid tumor (T#1388, Table 2Citation ) had one cycle of chemotherapy during infancy but persistent disease managed without cytotoxic therapy, finally undergoing definitive resection of viable tumor at 3 years of age. One INSS stage 4 infant (T#2117, Table 2Citation ) was managed with multimodality therapy and has residual but nonprogressing tumor 6 years after diagnosis and 4 years since last chemotherapy. One patient presented at 13 months of age with abdominal primary and distant lymph node metastasis (INSS stage 4), which was managed without cytotoxic therapy and spontaneously regressed (T#1940, Table 2Citation ). One 11-month-old with INSS stage 3, triploid NB was completely resected, managed with surgery alone, and doing well 7 years after diagnosis (T#987, Table 2Citation ). One infant stage 4 was MYCN amplified (T#1646, Table 2Citation ) and was managed with N7-type multimodality therapy (25) . This patient is alive and well, free of disease 3 years from diagnosis. Genetic group 1 therefore seems to distinguish a nonlethal form of NB (i.e., long-term survival).

Group 2.
This group had AI at 12q24 and/or 19q13 LOH. These genetic markers appear to be highly specific for this group because only one tumor (T#1379) from group 3 showed AI at 12q24 (in red, Table 2Citation ). All tumors in this group were intact at chromosomal arm 8qcen–q24, a marker with high frequency of AI in group 3 tumors (see below). Patients in this group presented with LR disease, refractory to multimodality therapy. Most slowly progressed over time into lethal stage 4 disease.

One patient had multiply recurrent, chemoresistant LR disease that evolved into metastatic disease to the bone marrow after 5 years (T#1163, Table 2Citation ). Two patients with INSS stage 3 disease at diagnosis (T#1637 and 1837) evolved to stage 4N disease within 1 year with distant lymph node metastasis but no bone or bone marrow involvement. One patient presented with INSS stage 1 tumor (T#1841, Table 2Citation ) managed without cytotoxic therapy but developed metastatic disease in liver and lungs 11 months later. One case (T#2116, Table 2Citation ) presented with INSS stage 2 disease managed without cytotoxic therapy and relapsed 2 years later with bone and lymph node metastasis. One case (T#1428, Table 2Citation ) with INSS stage 3 had multiply recurrent, refractory LR disease over the course of 3 years that eventually killed the patient. One case (T#1591) presented as INSS stage 3 and was MYCN amplified. Because of the MYCN status, this patient was treated with high-dose multimodality therapy from the beginning and did well. Genetic group 2 is composed predominantly of patients presenting with LR NB disease that is progressive and associated with poor survival.

Group 3.
All tumors in this group had AI at 8qcen–q24 or 10p11-p15 or both. Furthermore, all tumors had an intact 19q13, and all but one were also intact at 12q24.1 regions altered frequently in group 2 (Table 2)Citation . These patients predominantly presented with stage 4 disease and MYCN amplification (>10 copies/haploid genome; 6 of 7), a classically lethal form of NB. Only one case (T#2019) did not match the clinical pattern, although the tumor had 8q AI characteristic of this group. This patient presented at very young age, 3 months, with a LR tumor in the chest that was treated surgically. MYCN was not amplified. No cytotoxic therapy was given, and residual local [131I]metaiodobenzylguanidine-positive lymph nodes continued to improve. This patient is alive and well 18 months from diagnosis. Genetic group 3 seems to be a profile associated with stage 4, MYCN-amplified NB.


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Genome-wide allelotype analysis of tumor DNA was first performed for colorectal cancer (26) . Since then this approach has been used to study carcinomas of the lung (27 , 28) , nasopharynx (29) , esophagus (30 , 31) , cervix (32) , endometrium (33) , kidney (34) , breast (35 , 36) , pheochromocytomas and medullary thyroid carcinomas (37) , pituitary tumors (38) , childhood brain tumors (39) , and acute lymphoblastic leukemia (40 , 41) and has successfully contributed to the isolation of several tumor suppressor genes (42 , 43) . The recent development of semiautomated techniques using fluorescent-labeled primers for the genotyping of microsatellites has allowed high-resolution screening.

Previous allelotypic analyses of NB have been restricted primarily to particular chromosomal regions or arms (7, 8, 9, 10, 11, 12, 13 , 20, 21, 22 , 44 , 45) . Our results thus represent, to date, the highest resolution genome-wide NB allelotyping and allow for the determination of loci interactions. It was shown previously that chromosome arm 1p (multiple sites) and 17q have the most frequent AI (loss and gain, respectively) in NB (1, 2, 3 , 15) . Our results agree with and extend these findings. Overall, we found 11 different sites of frequent AI, 3 of them (8q, 10p, and 12q) not described previously in NB.

A new region of AI on chromosome 8q was found consistently centered around the microsatellite marker D8S1119 (ATA19G07; see Fig. 3Citation ). This marker4 has been well characterized cytogenetically at 8q21.3 and in the draft sequence comprises the chromosome 8: 99020313–99040347 base positions. One uncharacterized gene mapping in the region is AC084128.2 in the chromosome 8 clone CTD-3118D11. Nearby areas at 8q24 have been implicated in tumorigenesis. 8qcen–q24 gains have been described in Wilms’ tumors (46) , hepatoblastomas (47) , and germ cell tumors (48) . Furthermore, 8q gain was found to be of poor prognostic significance in a series of hepatoblastomas (47) . A few genes have been identified in this region including growth-related genes FGFR1; RAB4, a member of the RAS oncogene family; LYN, an v-yes-1 Yamaguchi sarcoma viral related gene; and others, TAGLN2, CYP7A1, SDCBP, and NSMAF, a sphingomyelinase activator factor. The results of our study show a high association between MYCN-amplified stage 4 tumors and 8q21.3 AI. Future investigations with higher resolution will therefore be crucial to narrow down the smallest common region of AI, and analysis should determine whether 8q21.3 AI corresponds to gain of genetic material as described previously in other childhood tumor types.

The new region of AI for NB on chromosome 10 is defined by three markers (see Fig. 3Citation ): (a) D10S1435 (or CHCL GATA88F09) at 10p15.1 and situated at chromosome 10 2607874–2627906; (b) D10S1430 (or CHCL GATA84C01) at 10p13, chromosome 10: 13308340–13508486. This marker has three nearby genes in the draft sequence, AL 512284.15, AC 026221.8, and AL 512783.16, all of unknown function; and (c) D10S1426 (or CHLC.GATA73E11) at 10p11.23, chromosome 10: 32735722–32936077 bp position. This new region is therefore a vast area from 10p11.23 to 10p15.1.5 Loss of an entire copy of chromosome 10 is common in tumors of the brain, lung, ovary, and skin (49) . Furthermore, in melanomas and gliomas, monosomy of chromosome 10 is an indicator of poor clinical prognosis (50 , 51) . In these tumor types, two regions at 10p15 and 10q have been described. Three tumor suppressor genes have been identified in the long arm of chromosome 10, PTEN (52) , DBMT1 (53) , and LGI1 (54) but none in the short arm. Very few genes have been isolated in this region but include IDI1, AKR1C3, DDH1, NET1A, PRKCQ, and the GATA-binding protein 3. In our study, LOH at chromosome 10 was found exclusively at 10p11.23–p15.1 and was associated with MYCN-amplified stage 4 tumors.

The new region of AI on chromosome 12 is defined by the consensus marker D12S395 (or CHLC.GATA4H01.523) cytogenetically mapping at 12q24.23 according to the draft sequence.5 The mapping position at chromosome 12 is 137873902–138074246r. 12q24 is a common breakpoint region for balanced and unbalanced translocations in many hematological malignancies6 and the site of genes involved in neurological disorders like spinocerebellar ataxia type 2 (ataxin-2) and phenylketonuria (phenylalanine hydroxylase gene); genes involved in signaling transduction and differentiation such as DTX1, CORO1C, and H11 genes; and the critical region for the Noonan syndrome (55, 56, 57, 58, 59) . Our results show 12q24.23 AI together with 19q13 LOH, as specific markers for high-risk LR NB.

NB is a heterogeneous disease with three clinically relevant categories derived from the natural history of the disease: (a) infants with widespread disease that can spontaneously regress without medical intervention (stage 4s); (b) LR disease that may recur but does not metastasize to bone or bone marrow (stages 1, 2, and 3); and (c) systemic disease with widespread metastasis that responds to cytotoxic therapy but frequently becomes resistant to medical treatment (stage 4). Efforts for a genetic classification of NB have been attempted in the past (60) ; however, the resulting groups did not entirely coincide with the risk categories used in clinical trials (i.e., COG), and they did not match with the natural history groups of disease either because metastatic (INSS stage 4) and nonmetastatic tumors (INSS stage 3) were grouped together. Many commonly altered regions, such as 1p36 LOH, 11q23 LOH, 14q32 LOH and 17q gain, can be detected in all risk categories of NB, as shown in this and previous reports (20 , 22) .

Experience in the last decade in our institution supports the hypothesis that the natural history of disease defines relevant clinical groups of NB and that there exist distinct molecular genetic profiles for each pattern of disease (20, 21, 22) . Therapeutic approaches can therefore be tailored for each group (61, 62, 63) . The results in this study identified novel regions of AI specifically associated with three distinct clinical patterns. This correlation illustrates the fundamental importance of having precise and complete clinical information in refining the genetic profiling of human cancers.

Two patients provided clinical exceptions to the genetic groups defined here and are worth further discussion. One case (tumor #2019) had some of the genetic characteristics of stage 4, MYCN-amplified tumors, i.e., 8q21.3 AI. This patient presented as a young infant with LR tumor, MYCN nonamplified, and is doing well with surgery alone, 1 year after diagnosis. The other case was also an infant with stage 4, MYCN-amplified disease (tumor #1646) managed with multimodality therapy because of the well-established risk factor, MYCN. The tumor, however, did not have the genetic characteristics of stage 4, MYCN-amplified tumors (group 3) but displayed features resembling that of group 1 tumors, the nonlethal form of NB. The patient is alive and well 3 years from diagnosis. It is likely that the clinical course of disease for NB is complex and dependent on many more factors than simply AI status. These factors are likely to include genetic alterations, age, and therapeutic approach. These exceptions to the genetic classification based on AI status raise the issue of cooperating factors and the effect of therapeutic intervention on the natural history of disease.

The role of the new regions of AI as clinical markers for high-risk tumors needs to be confirmed in a larger cohort of patients. Further studies to identify the relevant genes in each region may contribute to an understanding of the basic biology that underlies the clinical complexity of NB.


   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 This study was supported by Young Investigator Award YIA 2000 (to J. M.) from the American Society of Clinical Oncology. Presented in part at the 37th American Society of Clinical Oncology annual meeting, San Francisco, May 2001. Back

2 To whom requests for reprints should be addressed, at Department of Hematology and Oncology, Hospital Sant Joan de Deu de Barcelona, Passeig de Sant Joan de Deu num 2, 08950 Esplugues del Llobregat Barcelona, Spain. Phone: (34)-93-280-40-00, extension 2361; Fax: (34)-93-203-3959; E-mail: Jmora{at}hsjdbcn.org Back

3 The abbreviations used are: NB, neuroblastoma; LOH, loss of heterozygosity; FISH, fluorescence in situ hybridization; CGH, comparative genomic hybridization; AI, allelic imbalance; INSS, International Neuroblastoma Staging System; LR, local-regional. Back

4 MIT chromosome 8 genetic map: http://carbon.wi.mit.edu and http://genome.ucsc.edu/goldenPath/hgTracks.htmland. Back

5 Internet address: http://genome.ucsc.edu/goldenPath/hgTracks.htmland. Back

6 Internet address: http://cgap.nci.nih.gov/Chromosomes. Back

Received 7/16/01. Accepted 1/17/02.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Brodeur G. M., Sekhon G. S., Goldstein M. N. Chromosomal aberrations in human neuroblastomas. Cancer (Phila.), 40: 2256-2263, 1977.[Medline]
  2. Brodeur G. M., Green A. A., Hayes F. A., Williams K. J., Williams D. L., Tsiatis A. A. Cytogenetic features of human neuroblastomas and cell lines. Cancer Res., 41: 4678-4686, 1981.[Abstract/Free Full Text]
  3. Gilbert F., Feder M., Balaban G., et al Human neuroblastomas and abnormalities of chromosomes 1 and 17. Cancer Res., 44: 5444-5449, 1984.[Abstract/Free Full Text]
  4. Haag M. M., Soukup S. W., Neely J. E. Chromosome analysis of a human neuroblastoma. Cancer Res., 41: 2995-2999, 1981.[Abstract/Free Full Text]
  5. Biedler J. L., Spengler B. A. Human neuroblastoma cytogenetics Evans A. E. eds. . Advances in Neuroblastoma Research, : 81-96, Raven Press New York 1980.
  6. Brodeur G. M., Seeger R. C., Schwab M., Varmus H. E., Bishop J. M. Amplification of N-myc in untreated human neuroblastomas correlates with advanced stage disease. Science (Wash. DC), 224: 1121-1124, 1984.[Abstract/Free Full Text]
  7. Fong C. T., White P. S., Peterson K., Sapienza C., Cavenee W. K., Kern S. E., Vogelstein B., Cantor A. B., Look A. T., Brodeur G. M. Loss of heterozygosity for chromosomes 1 or 14 defines subsets of advanced neuroblastomas. Cancer Res., 52: 1780-1785, 1992.[Abstract/Free Full Text]
  8. Ejeskar K., Aburatani H., Abrahamsson J., Kogner P., Martinsson T. Loss of heterozygosity of 3p markers in neuroblastoma tumours implicate a tumor-suppressor locus distal to the FHIT gene. Br. J. Cancer, 77: 1787-1791, 1998.[Medline]
  9. Caron H., van Sluis P., Buschman R., Pereira do Tanque R., Maes P., Beks L., de Kraker J., Voute P. A., Vergnaud G., Westerveld A., Slater R., Versteeg R. Allelic loss of the short arm of chromosome 4 in neuroblastoma suggests a novel tumor suppressor gene locus. Hum. Genet., 97: 834-837, 1996.[Medline]
  10. Marshall B., Isidro G., Martins A. G., Boavida M. G. Loss of heterozygosity at chromosome 9p21 in primary neuroblastomas: evidence for two deleted regions. Cancer Genet. Cytogenet., 96: 134-139, 1997.[Medline]
  11. Weiss M. J., Guo C., Shusterman S., Hii G., Mirensky T. L., White P. S., Hogarty M. D., Rebbeck T. R., Teare D., Urbanek M., Brodeur G. M., Maris J. M. Localization of a hereditary neuroblastoma predisposition gene to 16p12–p13. Med. Pediatr. Oncol., 35: 526-530, 2000.[Medline]
  12. Meltzer S. J., O’Doherty S. P., Frantz C. N., Smolinski K., Yin J., Cantor A. B., Liu J., Valentine M., Brodeur G. M., Berg P. E. Allelic imbalance on chromosome 5q predicts long-term survival in neuroblastoma. Br. J. Cancer, 74: 1855-1861, 1996.[Medline]
  13. Takita J., Hayashi Y., Takei K., Yamaguchi N., Hanada R., Yamamoto K., Yokota J. Allelic imbalance on chromosome 18 in neuroblastoma. Eur. J. Cancer, 36: 508-513, 2000.
  14. Van Roy N., Jauch A., Van Gele M., Laureys G., Versteeg R., De Paepe A., Cremer T., Speleman F. Comparative genomic hybridization analysis of human neuroblastomas: detection of distal 1p deletions and further molecular genetic characterization of neuroblastoma cell lines. Cancer Genet. Cytogenet., 97: 135-142, 1997.[Medline]
  15. Plantaz D., Mohapatra G., Matthay K. K., Pellarin M., Seeger R. C., Feuerstein B. G. Gain of chromosome 17 is the most frequent abnormality detected in neuroblastoma by comparative genomic hybridization. Am. J. Pathol., 150: 81-89, 1997.[Abstract]
  16. Lo Cunsolo C., Bicocchi M. P., Petti A. R., Tonini G. P. Numerical and structural aberrations in advanced neuroblastoma tumours by CGH analysis: survival correlates with chromosome 17 status. Br. J. Cancer, 83: 1295-1300, 2000.[Medline]
  17. Van Roy N., Van Limbergen H., Vandesompele J., Van Gele M., Poppe B., Salwen H., Laureys G., Manoel N., De Paepe A., Speleman F Combined M-FISH and CGH analysis allows comprehensive description of genetic alterations in neuroblastoma cell lines. Genes Chromosomes Cancer, 32: 126-135, 2001.[Medline]
  18. Takita J., Hayashi Y., Kohno T., Shiseki M., Yamaguchi N., Hanada R., Yamamoto K., Yokota J. Allelotype of neuroblastoma. Oncogene, 11: 1829-1834, 1995.[Medline]
  19. Brodeur G. M., Pritchard J., Berthold F., Carlsen N. L., Castel V., Castelberry R. P., De Bernardi B., Evans A. E., Favrot M., Hedborg F., Kaneko M., Kemshead J., Lampert F., Lee R. E. J., Look T., Pearson A. D. J., Philip T., Roald B., Sawada T., Seeger R. C., Tsuchida Y., Voute P. A. Revisions of the International Criteria for neuroblastoma diagnosis, staging, and response to treatment. J. Clin. Oncol., 11: 1466-1477, 1993.[Abstract/Free Full Text]
  20. Mora J., Cheung N. K., Kushner B. H., LaQuaglia M. P., Kramer K., Fazzari M., Heller G., Chen L., Gerald W. L. Clinical categories of neuroblastoma are associated with different patterns of loss of heterozygosity on chromosome arm 1p. J. Mol. Diag., 2: 1-9, 2000.[Free Full Text]
  21. Mora J., Cheung N. K., Chen L., Qin J., Gerald W. Loss of heterozygosity at 19q13.3 is associated with locally aggressive neuroblastoma. Clin. Cancer Res., 7: 1358-1361, 2001.[Abstract/Free Full Text]
  22. Mora J., Cheung N. K., Chen L., Qin J., Gerald W. Survival analysis of clinical, pathologic and genetic features in neuroblastoma presenting as local-regional disease. Cancer (Phila.), 91: 435-442, 2001.[Medline]
  23. Cher M. L., MacGrogan D., Bookstein R., Brown J. A., Jenkins R. B., Jensen R. H. Comparative genomic hybridization, allelic imbalance, and fluorescence in situ hybridization on chromosome 8 in prostate cancer. Genes Chromosomes Cancer, 11: 153-162, 1994.[Medline]
  24. Cawkwell L., Bell S. M., Lewis F. A., Dixon M. F., Taylor G. R., Quirke P. Rapid detection of allele loss in colorectal tumours using microsatellites and fluorescent DNA technology. Br. J. Cancer, 67: 1262-1267, 1993.[Medline]
  25. Walsh P. S., Erlich H. A., Higuchi R. Preferential PCR amplification of alleles: mechanisms and solutions. PCR Methods Appl., 1: 241 1998.
  26. Vogelstein B., Fearon E. R., Kern S. E., Hamilton S. R., Preisinger A. C., Nakamura Y., White R. Allelotype of colorectal carcinomas. Science (Wash. DC), 244: 207-211, 1989.[Abstract/Free Full Text]
  27. Sanchez-Cespedes M., Ahrendt S. A., Piantadosi S., Rosell R., Monzo M., Wu L., Westra W. H., Yang S. C., Jen J., Sidransky D. Chromosomal alterations in lung adenocarcinoma from smokers and nonsmokers. Cancer Res., 61: 1309-1313, 2001.[Abstract/Free Full Text]
  28. Girard L., Zochbauer-Muller S., Virmani A. K., Gazdar A. F., Minna J. D. Genome-wide allelotyping of lung cancer identifies new regions of allelic loss, differences between small cell lung cancer and non-small cell lung cancer, and loci clustering. Cancer Res., 60: 4894-4906, 2000.[Abstract/Free Full Text]
  29. Lo K. W., Teo P. M., Hui A. B., To K. F., Tsang Y. S., Chan S. Y., Mak K. F., Lee J. C., Huang D. P. High resolution allelotype of microdissected primary nasopharyngeal carcinoma. Cancer Res., 60: 3348-3353, 2000.[Abstract/Free Full Text]
  30. Dolan K., Garde J., Gosney J., Sissons M., Wright T., Kingsnorth A. N., Walker S. J., Sutton R., Meltzer S. J., Field J. K. Allelotype analysis of oesophageal adenocarcinoma: loss of heterozygosity occurs at multiple sites. Br. J. Cancer, 78: 950-957, 1998.[Medline]
  31. Hu N., Roth M. J., Polymeropolous M., Tang Z. Z., Emmert-Buck M. R., Wang Q. H., Goldstein A. M., Feng S. S., Dawsey S. M., Ding T., Zhuang Z. P., Han X. Y., Ried T., Giffen C., Taylor P. R. Identification of novel regions of allelic loss from a genomewide scan of esophageal squamous-cell carcinoma in a high-risk Chinese population. Genes Chromosomes Cancer, 27: 217-228, 2000.[Medline]
  32. Mitra A. B., Murty V. V., Li R. G., Pratap M., Luthra U. K., Chaganti R. S. Allelotype analysis of cervical carcinoma. Cancer Res., 54: 4481-4487, 1994.[Abstract/Free Full Text]
  33. Fujino T., Risinger J. I., Collins N. K., Liu F. S., Nishii H., Takahashi H., Westphal E. M., Barrett J. C., Sasaki H., Kohler M. F., Berchuck A., Boyd J. Allelotype of endometrial carcinoma. Cancer Res., 54: 4294-4298, 1994.[Abstract/Free Full Text]
  34. Thrash-Bingham C. A., Greenberg R. E., Howard S., Bruzel A., Bremer M., Goll A., Salazar H., Freed J. J., Tartof K. D. Comprehensive allelotyping of human renal cell carcinomas using microsatellite DNA probes. Proc. Natl. Acad. Sci. USA, 92: 2854-2858, 1995.[Abstract/Free Full Text]
  35. Kerangueven F., Noguchi T., Coulier F., Allione F., Wargniez V., Simony-Lafontaine J., Longy M., Jacquemier J., Sobol H., Eisinger F., Birnbaum D. Genome-wide search for loss of heterozygosity shows extensive genetic diversity of human breast carcinomas. Cancer Res., 57: 5469-5474, 1997.[Abstract/Free Full Text]
  36. Osborne R. J., Hamshere M. G. A genome-wide map showing common regions of loss of heterozygosity/allelic imbalance in breast cancer. Cancer Res., 60: 3706-3712, 2000.[Abstract/Free Full Text]
  37. Khosla S., Patel V. M., Hay I. D., Schaid D. J., Grant C. S., van Heerden J. A., Thibodeau S. N. Loss of heterozygosity suggests multiple genetic alterations in pheochromocytomas and medullary thyroid carcinomas. J. Clin. Investig., 87: 1691-1699, 1991.
  38. Clayton R. N., Pfeifer M., Atkinson A. B., Belchetz P., Wass J. A., Kyrodimou E., Vanderpump M., Simpson D., Bicknell J., Farrell W. E. Different patterns of allelic loss (loss of heterozygosity) in recurrent human pituitary tumors provide evidence for multiclonal origins. Clin. Cancer Res., 6: 3973-3982, 2000.[Abstract/Free Full Text]
  39. Blaeker H., Rasheed B. K., McLendon R. E., Friedman H. S., Batra S. K., Fuchs H. E., Bigner S. H. Microsatellite analysis of childhood brain tumors. Genes Chromosomes Cancer, 15: 54-63, 1996.[Medline]
  40. Takeuchi S., Bartram C. R., Wada M., Reiter A., Hatta Y., Seriu T., Lee E., Miller C. W., Miyoshi I., Koeffler H. P. Allelotype analysis of childhood acute lymphoblastic leukemia. Cancer Res., 55: 5377-5382, 1995.[Abstract/Free Full Text]
  41. Chambon-Pautas C., Cave H., Gerard B., Guidal-Giroux C., Duval M., Vilmer E., Grandchamp B. High-resolution allelotype analysis of childhood B-lineage acute lymphoblastic leukemia. Leukemia (Baltimore), 12: 1107-1113, 1998.[Medline]
  42. Hahn S. A., Schutte M., Hoque A. T., Moskaluk C. A., da Costa L. T., Rozenblum E., Weinstein C. L., Fischer A., Yeo C. J., Hruban R. H., Kern S. E. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science (Wash. DC), 271: 350-353, 1996.[Abstract]
  43. Steck P. A., Pershouse M. A., Jasser S. A., Yung W. K., Lin H., Ligon A. H., Langford L. A., Baumgard M. L., Hattier T., Davis T., Frye C., Hu R., Swedlund B., Teng D. H., Tavtigian S. V. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat. Genet., 15: 356-362, 1997.[Medline]
  44. Janoueix-Lerosey I., Penther D., Thioux M., de Cremoux P., Derre J., Ambros P., Vielh P., Benard J., Aurias A., Delattre O. Molecular analysis of chromosome arm 17q gain in neuroblastoma. Genes Chromosomes Cancer, 28: 276-284, 2000.[Medline]
  45. White P., Maris J. M., Beltinger C., Sulman E., Marshall H. N., Fujimori M., Kaufman B. A., Biegel J. A., Allen C., Hilliard C., et al A region of consistent deletion in neuroblastoma maps within human chromosome 1p36.2–36.2. Proc. Natl. Acad. Sci. USA, 92: 5520-5524, 1995.[Abstract/Free Full Text]
  46. Getman M. E., Houseal T. W., Miller G. A., Grundy P. E., Cowell J. K., Landes G. M. Comparative genomic hybridization and its application to Wilms’ tumorigenesis. Cytogenet. Cell Genet., 82: 284-290, 1998.[Medline]
  47. Weber R. G., Pietsch T., von Schweinitz D., Lichter P. Characterization of genomic alterations in hepatoblastomas. A role for gains on chromosomes 8q and 20 as predictors of poor outcome. Am. J. Pathol., 157: 571-578, 2000.[Abstract/Free Full Text]
  48. Riopel M. A., Spellerberg A., Griffin C. A., Perlman E. J. Genetic analysis of ovarian germ cell tumors by comparative genomic hybridization. Cancer Res., 58: 3105-3110, 1998.[Abstract/Free Full Text]
  49. Mertens F., Johansson B., Hoglund M., Mitelman F. Chromosomal imbalance maps of malignant solid tumors: a cytogenetic survey of 3185 neoplasms. Cancer Res., 57: 2765-2780, 1997.[Abstract/Free Full Text]
  50. Robertson G. P., Herbst R. A., Nagane M., Huang H. J., Cavenee W. K. The chromosome 10 monosomy common in human melanomas results from loss of two separate tumor suppressor loci. Cancer Res., 59: 3596-35601, 1999.[Abstract/Free Full Text]
  51. Balesaria S., Brock C., Bower M., Clark J., Nicholson S. K., Lewis P., de Sanctis S., Evans H., Peterson D., Mendoza N., Glaser M. G., Newlands E. S., Fisher R. A. Loss of chromosome 10 is an independent prognostic factor in high-grade gliomas. Br. J. Cancer, 81: 1371-1377, 1999.[Medline]
  52. Li J., Yen C., Liaw D., Podsypanina K., Bose S., Wang S. I., Puc J., Miliaresis C., Rodgers L., McCombie R., Bigner S. H., Giovanella B. C., Ittmann M., Tycko B., Hibshoosh H., Wigler M. H., Parsons R. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science (Wash. DC), 275: 1943-1947, 1997.[Abstract/Free Full Text]
  53. Mollenhauer J., Wiemann S., Scheurlen W., Korn B., Hayashi Y., Wilgenbus K. K., von Deimling A., Poustka A. DMBT1, a new member of the SRCR superfamily, on chromosome 10q25.3–26.1 is deleted in malignant brain tumours. Nat. Genet., 17: 32-39, 1997.[Medline]
  54. Chernova O. B., Somerville R. P., Cowell J. K. A novel gene, LGI1, from 10q24 is rearranged and downregulated in malignant brain tumors. Oncogene, 17: 2873-2881, 1998.[Medline]
  55. Kenmochi N., Yoshihama M., Higa S., Tanaka T. The human ribosomal protein L6 gene in a critical region for Noonan syndrome. J. Hum. Genet., 45: 290-293, 2000.[Medline]
  56. Lee L., Dowhanick-Morrissette J., Katz A., Jukofsky L., Krantz I. D. Chromosomal localization, genomic characterization, and mapping to the Noonan syndrome critical region of the human Deltex (DTX1) gene. Hum. Genet., 107: 577-581, 2000.[Medline]
  57. Iizaka M., Han H. J., Akashi H., Furukawa Y., Nakajima Y., Sugano S., Ogawa M., Nakamura Y. Isolation and chromosomal assignment of a novel human gene, CORO1C, homologous to coronin-like actin-binding proteins. Cytogenet. Cell Genet., 88: 221-224, 2000.[Medline]
  58. Matsuura T., Sasaki H., Yabe I., Hamada K., Hamada T., Shitara M., Tashiro K. Mosaicism of unstable CAG repeats in the brain of spinocerebellar ataxia type 2. J. Neurol., 246: 835-839, 1999.[Medline]
  59. Erlandsen H., Stevens R. C. The structural basis of phenylketonuria. Mol. Genet. Metab., 68: 103-125, 1999.[Medline]
  60. Brodeur G. M., Azar C., Brother M., Hiemstra J., Kaufman B., Marshall H., Moley J., Nakagawara A., Saylors R., Scavarda N., et al Neuroblastoma: effect of genetic factors on prognosis and treatment. Cancer (Phila.), 70: 1685-1694, 1992.[Medline]
  61. Cheung N. K. V., Kushner B. H., LaQuaglia M. P., Kramer K., Gollamudi S., Heller G., Gerald W., Yeh S., Finn R., Larson S. M., Wuest D., Byrnes M., Dantis E., Mora J., Cheung I. Y., Rosenfield H., Abramson S., O’Reilly R. J. N7: a novel multi-modality therapy of high risk neuroblastoma in children diagnosed over 1 year of age. Med. Pediat. Oncol., 36: 227-230, 2001.[Medline]
  62. Cheung N. K., Kushner B. H., La Quaglia M. P., Kramer K., Ambros P., Ambros I., Ladanyi M., Eddy J., Bonilla M. A., Gerald W. Survival from non-stage 4 neuroblastoma without cytotoxic therapy: an analysis of clinical and biological markers. Eur. J. Cancer, 33: 2117-2119, 1997.
  63. Cheung N. K. V., Kushner B. H., Kramer K. Monoclonal antibody-based therapy of neuroblastoma Coppes M. Arceci R. eds. . Hematology/Oncology Clinics of North America, 15: 853-866, 2001.[Medline]



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