Diskin SJ, Capasso M, Diamond M, et al.
Rare variants in TP53 and susceptibility to neuroblastoma.
J Natl Cancer Inst. 2014; 106(4):dju047 [PubMed] Article available free on PMC after 01/04/2015 Related Publications

TP53 is the most frequently mutated gene in human malignancies; however, de novo somatic mutations in childhood embryonal cancers such as neuroblastoma are rare. We report on the analysis of three independent case-control cohorts comprising 10290 individuals and demonstrate that rs78378222 and rs35850753, rare germline variants in linkage disequilibrium that map to the 3' untranslated region (UTR) of TP53 and 5' UTR of the Δ133 isoform of TP53, respectively, are robustly associated with neuroblastoma (rs35850753: odds ratio [OR] = 2.7, 95% confidence interval [CI] = 2.0 to 3.6, P combined = 3.43×10(-12); rs78378222: OR = 2.3, 95% CI = 1.8 to 2.9, P combined = 2.03×10(-11)). All statistical tests were two-sided. These findings add neuroblastoma to the complex repertoire of human cancers influenced by the rs78378222 hypomorphic allele, which impairs proper termination and polyadenylation of TP53 transcripts. Future studies using whole-genome sequencing data are likely to reveal additional rare variants with large effect sizes contributing to neuroblastoma tumorigenesis.

Related: Neuroblastoma TP53

Capasso M, Diskin SJ, Totaro F, et al.
Replication of GWAS-identified neuroblastoma risk loci strengthens the role of BARD1 and affirms the cumulative effect of genetic variations on disease susceptibility.
Carcinogenesis. 2013; 34(3):605-11 [PubMed] Article available free on PMC after 01/04/2015 Related Publications

Several neuroblastoma (NB) susceptibility loci have been identified within LINC00340, BARD1, LMO1, DUSP12, HSD17B12, DDX4, IL31RA, HACE1 and LIN28B by genome-wide association (GWA) studies including European American individuals. To validate and comprehensively evaluate the impact of the identified NB variants on disease risk and phenotype, we analyzed 16 single nucleotide polymorphisms (SNPs) in an Italian population (370 cases and 809 controls). We assessed their regulatory activity on gene expression in lymphoblastoid (LCLs) and NB cell lines. We evaluated the cumulative effect of the independent loci on NB risk and high-risk phenotype development in Italian and European American (1627 cases and 2575 controls) populations. All NB susceptibility genes replicated in the Italian dataset except for DDX4 and IL31RA, and the most significant SNP was rs6435862 in BARD1 (P = 8.4 × 10(-15)). BARD1 showed an additional and independent SNP association (rs7585356). This variant influenced BARD1 mRNA expression in LCLs and NB cell lines. No evidence of epistasis among the NB-associated variants was detected, whereas a cumulative effect of risk variants on NB risk (European Americans: P (trend) = 6.9 × 10(-30), Italians: P (trend) = 8.55 × 10(13)) and development of high-risk phenotype (European Americans: P (trend) = 6.9 × 10(-13), Italians: P (trend) = 2.2 × 10(-1)) was observed in a dose-dependent manner. These results provide further evidence that the risk loci identified in GWA studies contribute to NB susceptibility in distinct populations and strengthen the role of BARD1 as major genetic contributor to NB risk. This study shows that even in the absence of interaction the combination of several low-penetrance alleles has potential to distinguish subgroups of patients at different risks of developing NB.

Related: Neuroblastoma BARD1

Owens C, Irwin M
Neuroblastoma: the impact of biology and cooperation leading to personalized treatments.
Crit Rev Clin Lab Sci. 2012 May-Jun; 49(3):85-115 [PubMed] Related Publications

Neuroblastoma is the most common extra-cranial solid tumor in children. It is a heterogeneous disease, consisting of neural crest-derived tumors with remarkably different clinical behaviors. It can present in a wide variety of ways, including lesions which have the potential to spontaneously regress, or as an extremely aggressive form of metastatic cancer which is resistant to all forms of modern therapy. They can arise anywhere along the sympathetic nervous system. The median age of presentation is approximately 18 months of age. Urinary catecholamines (HVA and VMA) are extremely sensitive and specific tumor markers and are used in diagnosis, treatment response assessment and post-treatment surveillance. The largest national treatment groups from North America, Europe and Japan have formed the International Neuroblastoma Risk Group Task Force (INRG) to identify prognostic factors, to understand the mechanisms of tumorigenesis in this rare disease and to develop multi-modality therapies to improve outcomes and decrease treatment-related toxicities. This international cooperation has resulted in a significant leap in our understanding of the molecular pathogenesis of neuroblastoma. Lower staged disease can be cured if the lesion is resectable. Treatment of unresectable disease (loco-regional and metastatic) is stratified depending on clinical features (age at presentation, staging investigations) and specific tumor biological markers that include histopathological analyses, chromosomal abnormalities and the quantification of expression of an oncogene (MYCN). Modern treatment of high-risk neuroblastoma is the paradigm for the evolution of therapy in pediatric oncology. Outcomes have improved substantially with multi-modality therapy, including chemotherapy, surgery, radiation therapy, myeloablative therapy with stem cell transplant, immunotherapy and differentiation therapy; these comprise the standard of care worldwide. In addition, newer targeted therapies are being tested in phase I/II trials. If successful these agents will be incorporated into mainstream treatment programs.

Related: Neuroblastoma NTRK1 gene MYCN (n-myc)

Bosse KR, Diskin SJ, Cole KA, et al.
Common variation at BARD1 results in the expression of an oncogenic isoform that influences neuroblastoma susceptibility and oncogenicity.
Cancer Res. 2012; 72(8):2068-78 [PubMed] Article available free on PMC after 01/04/2015 Related Publications

The mechanisms underlying genetic susceptibility at loci discovered by genome-wide association study (GWAS) approaches in human cancer remain largely undefined. In this study, we characterized the high-risk neuroblastoma association at the BRCA1-related locus, BARD1, showing that disease-associated variations correlate with increased expression of the oncogenically activated isoform, BARD1β. In neuroblastoma cells, silencing of BARD1β showed genotype-specific cytotoxic effects, including decreased substrate-adherence, anchorage-independence, and foci growth. In established murine fibroblasts, overexpression of BARD1β was sufficient for neoplastic transformation. BARD1β stabilized the Aurora family of kinases in neuroblastoma cells, suggesting both a mechanism for the observed effect and a potential therapeutic strategy. Together, our findings identify BARD1β as an oncogenic driver of high-risk neuroblastoma tumorigenesis, and more generally, they illustrate how robust GWAS signals offer genomic landmarks to identify molecular mechanisms involved in both tumor initiation and malignant progression. The interaction of BARD1β with the Aurora family of kinases lends strong support to the ongoing work to develop Aurora kinase inhibitors for clinically aggressive neuroblastoma.

Related: Apoptosis Neuroblastoma BARD1

Lau DT, Norris MD, Marshall GM, et al.
HLA-G polymorphisms, genetic susceptibility, and clinical outcome in childhood neuroblastoma.
Tissue Antigens. 2011; 78(6):421-7 [PubMed] Related Publications

Neuroblastoma is the most common solid tumor in children less than 5 years of age. The early onset of neuroblastoma suggests that genes involved in fetal development and pregnancy may have a putative role in the etiology of neuroblastoma. The human leukocyte antigen subtype G (HLA-G) molecule plays an important role in immune response regulation and appears to regulate immune tolerance during early pregnancy as well as tumor immunosurveillance. Elevated levels of soluble HLA-G (sHLA-G) have been detected in a number of malignancies including serum samples from neuroblastoma and have been reported to be predictive of tumor relapse in neuroblastoma. In light of previous investigations suggesting that single nucleotide polymorphisms in the HLA-G gene may impact on protein expression levels and isoform production, we examined the influence of HLA-G polymorphisms on the susceptibility and clinical outcome of neuroblastoma in 163 neuroblastoma patients and 404 healthy controls. The distribution of HLA-G polymorphisms, alleles, or allelic groups did not differ between children diagnosed with neuroblastoma and healthy controls. Our analyses did not detect an association between common HLA-G polymorphisms and clinical outcome in patients treated for neuroblastoma.

Related: Neuroblastoma

Devoto M, Specchia C, Laudenslager M, et al.
Genome-wide linkage analysis to identify genetic modifiers of ALK mutation penetrance in familial neuroblastoma.
Hum Hered. 2011; 71(2):135-9 [PubMed] Article available free on PMC after 01/04/2015 Related Publications

BACKGROUND: Neuroblastoma (NB) is an important childhood cancer with a strong genetic component related to disease susceptibility. Approximately 1% of NB cases have a positive family history. Following a genome-wide linkage analysis and sequencing of candidate genes in the critical region, we identified ALK as the major familial NB gene. Dominant mutations in ALK are found in more than 50% of familial NB cases. However, in the families used for the linkage study, only about 50% of carriers of ALK mutations are affected by NB.
METHODS: To test whether genetic variation may explain the reduced penetrance of the disease phenotype, we analyzed genome-wide genotype data in ALK mutation-positive families using a model-based linkage approach with different liability classes for carriers and non-carriers of ALK mutations.
RESULTS: The region with the highest LOD score was located at chromosome 2p23-p24 and included the ALK locus under models of dominant and recessive inheritance.
CONCLUSIONS: This finding suggests that variants in the non-mutated ALK gene or another gene linked to it may affect penetrance of the ALK mutations and risk of developing NB in familial cases.

Related: Chromosome 2 Neuroblastoma

Nguyen le B, Diskin SJ, Capasso M, et al.
Phenotype restricted genome-wide association study using a gene-centric approach identifies three low-risk neuroblastoma susceptibility Loci.
PLoS Genet. 2011; 7(3):e1002026 [PubMed] Article available free on PMC after 01/04/2015 Related Publications

Neuroblastoma is a malignant neoplasm of the developing sympathetic nervous system that is notable for its phenotypic diversity. High-risk patients typically have widely disseminated disease at diagnosis and a poor survival probability, but low-risk patients frequently have localized tumors that are almost always cured with little or no chemotherapy. Our genome-wide association study (GWAS) has identified common variants within FLJ22536, BARD1, and LMO1 as significantly associated with neuroblastoma and more robustly associated with high-risk disease. Here we show that a GWAS focused on low-risk cases identified SNPs within DUSP12 at 1q23.3 (P = 2.07 × 10⁻⁶), DDX4 and IL31RA both at 5q11.2 (P = 2.94 × 10⁻⁶ and 6.54 × 10⁻⁷ respectively), and HSD17B12 at 11p11.2 (P = 4.20 × 10⁻⁷) as being associated with the less aggressive form of the disease. These data demonstrate the importance of robust phenotypic data in GWAS analyses and identify additional susceptibility variants for neuroblastoma.

Related: Neuroblastoma

Wang K, Diskin SJ, Zhang H, et al.
Integrative genomics identifies LMO1 as a neuroblastoma oncogene.
Nature. 2011; 469(7329):216-20 [PubMed] Article available free on PMC after 01/04/2015 Related Publications

Neuroblastoma is a childhood cancer of the sympathetic nervous system that accounts for approximately 10% of all paediatric oncology deaths. To identify genetic risk factors for neuroblastoma, we performed a genome-wide association study (GWAS) on 2,251 patients and 6,097 control subjects of European ancestry from four case series. Here we report a significant association within LIM domain only 1 (LMO1) at 11p15.4 (rs110419, combined P = 5.2 × 10(-16), odds ratio of risk allele = 1.34 (95% confidence interval 1.25-1.44)). The signal was enriched in the subset of patients with the most aggressive form of the disease. LMO1 encodes a cysteine-rich transcriptional regulator, and its paralogues (LMO2, LMO3 and LMO4) have each been previously implicated in cancer. In parallel, we analysed genome-wide DNA copy number alterations in 701 primary tumours. We found that the LMO1 locus was aberrant in 12.4% through a duplication event, and that this event was associated with more advanced disease (P < 0.0001) and survival (P = 0.041). The germline single nucleotide polymorphism (SNP) risk alleles and somatic copy number gains were associated with increased LMO1 expression in neuroblastoma cell lines and primary tumours, consistent with a gain-of-function role in tumorigenesis. Short hairpin RNA (shRNA)-mediated depletion of LMO1 inhibited growth of neuroblastoma cells with high LMO1 expression, whereas forced expression of LMO1 in neuroblastoma cells with low LMO1 expression enhanced proliferation. These data show that common polymorphisms at the LMO1 locus are strongly associated with susceptibility to developing neuroblastoma, but also may influence the likelihood of further somatic alterations at this locus, leading to malignant progression.

Related: Chromosome 11 Neuroblastoma LMO1

Capasso M, Diskin SJ
Genetics and genomics of neuroblastoma.
Cancer Treat Res. 2010; 155:65-84 [PubMed] Related Publications

Neuroblastoma is a pediatric cancer of the developing sympathetic nervous system that most often affects young children. It remains an important pediatric problem because it accounts for approximately 15% of childhood cancer mortality. The disease is clinically heterogeneous, with the likelihood of cure varying greatly according to age at diagnosis, extent of disease, and tumor biology. This extreme clinical heterogeneity reflects the complexity of genetic and genomic events associated with development and progression of disease. Inherited genetic variants and mutations that initiate tumorigenesis have been identified in neuroblastoma and multiple somatically acquired genomic alterations have been described that are relevant to disease progression. This chapter focuses on recent genome-wide studies that have utilized high-density single nucleotide polymorphism (SNP) genotyping arrays to discover genetic factors predisposing to tumor initiation such as rare mutations at locus 2p23 (in ALK gene) for familial neuroblastoma, common SNPs at 6p22 (FLJ22536 and FLJ44180) and 2q35 (BARD1), and a copy number polymorphism at 1q21.1 (NBPF23) for sporadic neuroblastoma. It also deals with well known and recently reported somatic changes in the tumor genome such as mutations, gain of alleles and activation of oncogenes, loss of alleles, or changes in tumor-cell ploidy leading to the diverse clinical behavior of neuroblastomas. Finally, this chapter reviews gene expression profiles of neuroblastoma associated with pathways of the signaling of neurotrophins and apoptotic factors that could have a role in neuroblastoma development and progression. Looking forward, a major challenge will be to understand how inherited genetic variation and acquired somatic alterations in the tumor genome interact to exact phenotypic differences in neuroblastoma, and cancer in general.

Related: Neuroblastoma

Janoueix-Lerosey I, Schleiermacher G, Delattre O
Molecular pathogenesis of peripheral neuroblastic tumors.
Oncogene. 2010; 29(11):1566-79 [PubMed] Related Publications

Neuroblastoma (NB) is an embryonal cancer of the sympathetic nervous system observed in early childhood, characterized by a broad spectrum of clinical behaviors, ranging from spontaneous regression to fatal outcome despite aggressive therapies. NB accounts for 8-10% of pediatric cancers and 15% of the deaths attributable to malignant conditions in children. Interestingly, NB may occur in various contexts, being mostly sporadic but also familial or syndromic. This review focuses on recent advances in the identification of the genes and mechanisms implicated in NB pathogenesis. Although the extensive characterization of the genomic aberrations recurrently observed in sporadic NBs provides important insights into the understanding of the clinical heterogeneity of this neoplasm, analysis of familial and syndromic cases also unravels essential clues on the genetic bases of NB. Recently, the ALK gene emerged as an important NB gene, being implicated both in sporadic and familial cases. The identification of gene expression signatures associated with patient's outcome points out the potential of using gene expression profiling to improve clinical management of patients suffering from NB. Finally, based on recent observations integrating genomic analyses, biological data and clinical information, we discuss possible evolution/progression schemes in NB.

Related: Neuroblastoma PHOX2B

Abbaszadeh F, Barker KT, McConville C, et al.
A new familial cancer syndrome including predisposition to Wilms tumor and neuroblastoma.
Fam Cancer. 2010; 9(3):425-30 [PubMed] Related Publications

Wilms tumor and neuroblastoma are childhood tumors of the kidney and undifferentiated neural crest cells, respectively. Both disorders are primarily sporadic, but familial Wilms tumor pedigrees and familial neuroblastoma pedigrees are each well recognized and account for approximately 1-3% of each tumor type. Families with Wilms tumor and neuroblastoma in the same, or related individuals, have not been reported. Here, we present nine families with two or more individuals with Wilms tumor and/or neuroblastoma. The affected individuals were otherwise well, without syndromic features. Although this co-occurrence might be due to chance in some families, the coexistence of two rare embryonal tumors in related individuals of multiple families suggests an underlying genetic susceptibility to both tumors. We undertook mutational analysis of the genes known to predispose to non-syndromic familial Wilms tumor (WT1) or neuroblastoma (PHOX2B, ALK) which excluded these as the underlying predisposition genes in the nine families. We also excluded epigenetic and copy-number abnormalities at 11p15 which are known to predispose to embryonal tumors including Wilms tumor and neuroblastoma. Overall, these data suggest that families with both Wilms tumor and neuroblastoma represent a previously unrecognized familial cancer syndrome in which the underlying predisposition gene(s) remain to be determined.

Related: Neuroblastoma Wilms' Tumour Wilms Tumour PHOX2B

Mueller S, Matthay KK
Neuroblastoma: biology and staging.
Curr Oncol Rep. 2009; 11(6):431-8 [PubMed] Related Publications

Neuroblastoma is the most common extracranial tumor of childhood, with about 650 new cases each year in the United States. The clinical course of neuroblastoma is variable and depends on age at diagnosis, staging, histology, and specific genetic abnormalities, such as MYCN oncogene amplification or aberrations of chromosome 1p or 11q. A subset of tumors will undergo spontaneous regression, whereas others progress despite aggressive therapy. The varied clinical behavior reflects genetic heterogeneity, with many possible gene candidates identified in studies using comparative genetic hybridization arrays, RNA expression microarrays, and genome-wide association studies. Recent studies implicated the anaplastic lymphoma kinase gene in the tumorigenesis of many familial and some sporadic cases of neuroblastoma. The International Neuroblastoma Risk Group developed a new staging and risk classification, with recommendations for analysis of biological markers in neuroblastoma. This review discusses the biology of these tumors, current and new risk classification, and staging recommendations, with a brief outline of preferred treatment strategies.

Related: Chromosome 1 Chromosome 11 Neuroblastoma

Eng C
Cancer: A ringleader identified.
Nature. 2008; 455(7215):883-4 [PubMed] Related Publications

Related: Chromosome 2 Neuroblastoma

Nau JY
[Discovery of a gene mutation associated with familial neuroblastoma].
Rev Med Suisse. 2008; 4(169):1888 [PubMed] Related Publications

Related: Chromosome 2 France Neuroblastoma USA

Mossé YP, Laudenslager M, Longo L, et al.
Identification of ALK as a major familial neuroblastoma predisposition gene.
Nature. 2008; 455(7215):930-5 [PubMed] Article available free on PMC after 01/04/2015 Related Publications

Neuroblastoma is a childhood cancer that can be inherited, but the genetic aetiology is largely unknown. Here we show that germline mutations in the anaplastic lymphoma kinase (ALK) gene explain most hereditary neuroblastomas, and that activating mutations can also be somatically acquired. We first identified a significant linkage signal at chromosome bands 2p23-24 using a whole-genome scan in neuroblastoma pedigrees. Resequencing of regional candidate genes identified three separate germline missense mutations in the tyrosine kinase domain of ALK that segregated with the disease in eight separate families. Resequencing in 194 high-risk neuroblastoma samples showed somatically acquired mutations in the tyrosine kinase domain in 12.4% of samples. Nine of the ten mutations map to critical regions of the kinase domain and were predicted, with high probability, to be oncogenic drivers. Mutations resulted in constitutive phosphorylation, and targeted knockdown of ALK messenger RNA resulted in profound inhibition of growth in all cell lines harbouring mutant or amplified ALK, as well as in two out of six wild-type cell lines for ALK. Our results demonstrate that heritable mutations of ALK are the main cause of familial neuroblastoma, and that germline or acquired activation of this cell-surface kinase is a tractable therapeutic target for this lethal paediatric malignancy.

Related: Chromosome 2 Neuroblastoma

Cattelani S, Defferrari R, Marsilio S, et al.
Impact of a single nucleotide polymorphism in the MDM2 gene on neuroblastoma development and aggressiveness: results of a pilot study on 239 patients.
Clin Cancer Res. 2008; 14(11):3248-53 [PubMed] Related Publications

PURPOSE: MDM2 is a key negative regulator of p53 activity, and a single nucleotide polymorphism (SNP309, T>G change; rs 2279744) in its promoter increases the affinity for the transcription factor SP1, enhancing MDM2 expression. We carried out a pilot study to investigate the effect of this polymorphism on development and behavior of neuroblastoma, an extracranial pediatric tumor with unfrequent genetic inactivation of p53.
EXPERIMENTAL DESIGN: We genotyped the MDM2-SNP309 alleles of tumor DNA from 239 neuroblastoma patients and peripheral blood DNA from 237 controls. In 40 of 239 neuroblastomas, the MDM2-SNP309 alleles were also genotyped in peripheral blood DNA. Data were analyzed by two-sided Fisher's exact test, log-rank test, and Kaplan-Meier statistics. Where appropriate, data are reported with 95% confidence intervals (CI).
RESULTS: The frequency of both the T/G and G/G genotypes or the G/G or T/G genotype only was higher in neuroblastoma DNA samples than in controls: 60.3% (95% CI, 54.1-66.5) versus 47.3% (95% CI, 40.9-53.6), 30.4% (95% CI, 22.4-37.8) versus 15.0% (95% CI, 9.2-20.7), and 52.0% (95% CI, 45.0-59.9) versus 41.9% (95% CI, 35.3-48.5), respectively; Two-Sided Fisher's Exact Test P values were 0.006, 0.003, and 0.048, respectively; Odds ratios were 1.69 (95% CI, 1.18-2.43), 2.45 (95% CI, 1.37-4.39) and 1.51 (95% CI, 1.02-2.22), respectively. A significant association (P = 0.016) between heterozygous (T/G)/homozygous (G/G) genotypes at SNP309 and advanced clinical stages was also shown. Homozygous/heterozygous SNP309 variant carriers had a shorter 5-year overall survival than patients with the wild-type allele (P = 0.046; log-rank test). A shorter overall survival in patients with heterozygous/homozygous SNP309 was also observed in the subgroups with age at diagnosis >1 year and adrenal primary tumor (P = 0.024 and P = 0.014, respectively).
CONCLUSIONS: Data from this pilot study suggest that the MDM2 G/G and T/G-SNP309 alleles are markers of increased predisposition to tumor development and disease aggressiveness in neuroblastoma. However, additional studies with larger patient cohorts are required for a definitive assessment of the clinical relevance of these data.

Related: Neuroblastoma MDM2 gene

de Pontual L, Trochet D, Bourdeaut F, et al.
Methylation-associated PHOX2B gene silencing is a rare event in human neuroblastoma.
Eur J Cancer. 2007; 43(16):2366-72 [PubMed] Related Publications

Neuroblastoma (NB), an embryonic tumour originating from neural crest cells, is one of the most common solid tumours in childhood. Although NB is characterised by numerous recurrent, large-scale chromosome rearrangements, the genes targeted by these imbalances have remained elusive. We recently identified the paired-like homeobox 2B (PHOX2B, MIM 603851) gene as disease-causing in dysautonomic disorders including Congenital Central Hypoventilation Syndrome (CCHS), Hirschsprung disease (HSCR) and NB in various combinations. Most patients with NB due to a germline heterozygous PHOX2B gene mutation are familial and/or syndromic. PHOX2B, at chromosome 4p12, does not lie in a commonly rearranged locus in NB. To evaluate the role of PHOX2B in sporadic, isolated NB, we analysed 13 NB cell lines and 45 tumours for expression, mutations of coding and promoter sequences, loss of heterozygosity (LOH), or aberrant hypermethylation of PHOX2B (13 cell lines and 18 tumours). We didn't identify any mutation but LOH in about 10% of the cases and aberrant CpG dinucleotide methylation of the 500 bp PHOX2B promoter region in 4/31 tumours and cell lines (12.9%). Altogether, both germinal and somatic anomalies at the PHOX2B locus are found in NB.

Related: Neuroblastoma PHOX2B

Longo L, Panza E, Schena F, et al.
Genetic predisposition to familial neuroblastoma: identification of two novel genomic regions at 2p and 12p.
Hum Hered. 2007; 63(3-4):205-11 [PubMed] Related Publications

OBJECTIVES: The rarity of familial neuroblastoma (NB) has allowed only a few linkage studies, most of which did not show any evidence of linkage to regions involved in somatic alterations or to genes implicated in other neurocristopathies seldom associated with NB. We screened a highly informative family with recurrent NB by genome-wide linkage analysis aimed at identifying chromosomal regions for NB predisposing genes.
METHODS: A genome-wide screen was performed using 382 microsatellite markers. Multipoint model-based linkage analysis was carried out under a dominant mode of inheritance for the disease using the 'affected only' approach.
RESULTS: Our analysis identified two haplotypes co-segregating with the disease on chromosomes 2p and 12p, and yielded maximum lod-score values of 3.01 (p < 0.0001) for markers on both intervals.
CONCLUSIONS: Evidence of linkage was reported at 16p in North American families, whereas our studies excluded this interval and indicated other loci for disease predisposition, thus confirming the remarkable genetic heterogeneity of NB. These results suggest an oligogenic inheritance in NB involving more loci in genetic determination of the disease.

Related: Chromosome 12 Chromosome 2 Neuroblastoma

Lanciotti M, Coco S, Michele PD, et al.
Glutathione S-transferase polymorphisms and susceptibility to neuroblastoma.
Pharmacogenet Genomics. 2005; 15(6):423-6 [PubMed] Related Publications

There is evidence to suggest that polymorphic variations in the glutathione S-transferase (GSTs) are associated with cancer susceptibility. The GST supergene family includes several genes with well characterized polymorphisms. Approximately 50% of the Caucasian population is homozygous for deletions in GSTM1 and approximately 20% are homozygous for deletions in GSTT1. Deletions lead to an absence of the protein, thus resulting in conjugation deficiency of mutagenic electrophiles to glutathione. The GSTP1 gene displays a polymorphism at codon 105 resulting in an Ile to Val substitution, which alters the enzymatic activity of the protein, and this has been suggested as a putative high-risk genotype in various cancers. In the present study, we investigated the relationship between GSTs polymorphism and the susceptibility to neuroblastoma, comparing GSTs genotypes of 256 children with neuroblastoma with those of 392 normal control subjects. No significant differences of allele frequencies were found between patients and controls. Within the neuroblastoma group, we further investigated whether any particular GSTs genotype was correlated with clinical and biological characteristics at diagnosis, but no association was detected. Our data do not support an important effect of GSTs genotype on neuroblastoma susceptibility.

Related: Neuroblastoma Polymorphisms

Perri P, Bachetti T, Longo L, et al.
PHOX2B mutations and genetic predisposition to neuroblastoma.
Oncogene. 2005; 24(18):3050-3 [PubMed] Related Publications

Neuroblastoma (NB) is a childhood malignancy originating from neural crest cells, which seldom occurs in association with other neurocristopathies. Owing to the rarity of familial NB cases, only a few linkage data are available and no mutations in candidate genes have been demonstrated up till now. Germline mutations in a small proportion of NB patients have been recently reported in the paired-like homeobox 2B (PHOX2B) gene, suggesting its role in NB predisposition. On the basis of this indication, we screened three Italian families with recurrence of NB and one family with occurrence of ganglioneuroblastoma and isolated Hirschsprung disease for PHOX2B defects. Our analysis did not show any mutation, excluding PHOX2B as the NB susceptibility gene in the families we analysed. Our findings combined with those derived from other PHOX2B mutation screenings and from genome-wide linkage analysis support a remarkable genetic heterogeneity of NB and suggest an oligogenic model of disease transmission. Furthermore, as PHOX2B mutations were mainly observed in some NB families with multifocal and syndromic NB, features that are missing in the families we have studied, we suggest they represent second-site modifications responsible for a specific phenotype rather than causal mutations of a major locus.

Related: Neuroblastoma PHOX2B

Mosse YP, Laudenslager M, Khazi D, et al.
Germline PHOX2B mutation in hereditary neuroblastoma.
Am J Hum Genet. 2004; 75(4):727-30 [PubMed] Article available free on PMC after 01/04/2015 Related Publications

Related: Neuroblastoma PHOX2B

Gripp KW, Kawame H, Viskochil DH, Nicholson L
Elevated catecholamine metabolites in patients with Costello syndrome.
Am J Med Genet A. 2004; 128A(1):48-51 [PubMed] Related Publications

Costello syndrome is a rare congenital anomaly syndrome with a predisposition to specific tumors, including neuroblastoma, rhabdomyosarcoma, and transitional cell carcinoma of the bladder. The increased risk for solid tumors led to the proposal of a tumor screening protocol. A screening test for neuroblastoma consists of measuring catecholamine metabolites in urine, an assay that may also be used for diagnostic confirmation of a suspected catecholamine secreting tumor. We report eight patients with Costello syndrome with elevated catecholamine metabolites, vanillylmandelic acid (VMA) and/or homovanillic acid (HVA), in urine. Each patient had additional laboratory and/or imaging studies. None of the patients was found to have a neuroblastoma or another catecholamine secreting tumor. In two cases, the assays were performed because the patients were symptomatic with diaphoresis and hypertension, respectively, and in the other six cases the assays were performed in order to screen for neuroblastoma. The pathophysiology for the catecholamine metabolite abnormality in these patients with Costello syndrome remains unclear. However, it appears that in this patient group an elevation above the normal limit, defined as 2 standard deviations (SD) above the mean for age, is more likely to be a variant, rather than a sign of a neuroblastoma. Thus, it may be prudent not to use this assay as a screening test, and to take the frequently elevated results into consideration when interpreting diagnostic assays.

Related: Neuroblastoma

Douc-Rasy S, Goldschneider D, Million K, Bénard J
[Interrelations between p73 and p53: a model, neuroblastoma].
Med Sci (Paris). 2004; 20(3):317-24 [PubMed] Related Publications

Homologies in sequence and gene organization of p53 and their relatives, p73 and p63, suggest similar biological functions. However differences exist between the p53 family members. Indeed in human tumors p53 is often mutated while p63 and p73 are very rarely mutated. In addition, in contrast to p53 which is transcribed in a unique mRNA species spanning all gene exons, each homologue expresses two types of isoforms: some with transactivation domain (TAD) showing tumor suppressive properties, the others deprived of TAD, with oncogenic properties. If p53 responds to immediate genotoxic stress, its homologues participate to the cell homeostasis of specific tissues along their development and differentiation, neuronal tissue for p73, epithelial for p63. However a collaboration between the three p53 family members has been shown to occur in response to cell genotoxic damages. Neuroblastic tumors characterized by a large spectrum of neuronal differentiation constitute a good model to study relationship between p73 and p53 as well as the regulation of their respective expression.

Related: Neuroblastoma TP73

Zimling ZG, Rechnitzer C, Rasmussen M, Petersen BL
Familial neuroblastoma - different histological manifestations in a family with three affected individuals.
APMIS. 2004; 112(2):153-8 [PubMed] Related Publications

Neuroblastoma is one of the most common malignant neoplasms in childhood. These tumours represent a heterogeneous group both in terms of clinical course and histological appearance, ranging from benign, slowly growing, often asymptomatic ganglioneuromas to malignant, highly aggressive neuroblastomas. Most cases occur sporadically, but in rare cases several individuals in the same family present with ganglioneuroblastomatous tumours. We report a case of familial neuroblastoma, occurring in a mother and her two daughters, with very different clinical presentation, outcome and tumour histology. The mother had recurrent, fully mature, benign ganglioneuromas, predominantly located in the retroperitoneum. The two daughters both developed malignant abdominal neuroblastomas, at the age of 2 and 8 years, respectively. Both died in spite of intensive therapy. Hereditary neuroblastoma appears to be as heterogeneous as the sporadic form of the disease. Since no consistent predisposition gene has been located in affected families, several different genetic or epigenetic events may account for the different histological and clinical presentations.

Related: FISH Neuroblastoma

Trochet D, Bourdeaut F, Janoueix-Lerosey I, et al.
Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma.
Am J Hum Genet. 2004; 74(4):761-4 [PubMed] Article available free on PMC after 01/04/2015 Related Publications

Neuroblastoma (NB) is a frequent pediatric tumor for which recurrent somatic rearrangements are known. Germline mutations of predisposing gene(s) are suspected on the basis of rare familial cases and the association of NB with other genetically determined congenital malformations of neural crest-derived cells--namely, Hirschsprung disease (HSCR) and/or congenital central hypoventilation syndrome (CCHS). We recently identified the paired-like homeobox 2B (PHOX2B) gene as the major disease-causing gene in isolated and syndromic CCHS, which prompted us to regard it as a candidate gene in NB. Here, we report on germline mutations of PHOX2B in both a familial case of NB and a patient with the HSCR-NB association. PHOX2B, therefore, stands as the first gene for which germline mutations predispose to NB.

Related: Neuroblastoma PHOX2B

Nakagawara A
Neural crest development and neuroblastoma: the genetic and biological link.
Prog Brain Res. 2004; 146:233-42 [PubMed] Related Publications

Neuroblastoma is one of the most common pediatric solid tumors originating from the sympathoadrenal lineage of neural crest. The tumor shows extremely different clinical phenotypes such as spontaneous regression on one hand and aggressive growth on the other hand. The different biological behavior of neuroblastoma appears to be determined by the genetic abnormalities including amplification of MYCN oncogene, DNA ploidy and some allelic imbalances. However, the spontaneous regression of neuroblastoma mimics the programmed cell death normally occurring in developing sympathetic cells expressing both TrkA tyrosine kinase A and p75NTR neurotrophin receptor. Indeed, TrkA expression is the most important factor related to the induction of tumor cell differentiation and/or programmed cell death because without its expression spontaneous regression of neuroblastoma never occurs. Thus, the enigmatic clinical behaviors of neuroblastoma are strictly linked to the molecular mechanism of neural crest development.

Related: Neuroblastoma NTRK1 gene Signal Transduction TP53 MYCN (n-myc) TP73

Tonini GP, Longo L, Coco S, Perri P
Familial neuroblastoma: a complex heritable disease.
Cancer Lett. 2003; 197(1-2):41-5 [PubMed] Related Publications

Genomic surveys carried out over the years have revealed a great heterogeneity in the pattern of genetic aberrations occurring in neuroblastoma (NB) cells. Studies on familial NB could lead to the discovery of susceptibility genes and their contribution to the development of the disease. The two-hit hypothesis is considered the most consistent model of inherited predisposition to NB, but an oligogenic inheritance governed by a major gene should be also taken into account. The rarity of familial clustering of NB cases and the difficulty to recruit informative families has not allowed the identification of the disease gene until now. In fact, linkage analysis has suggested more than one region candidate to harboring NB predisposing gene(s). These findings indicate that genetic heterogeneity might be the molecular basis of the disorder. Given the complexity of the disease additional studies are required to elucidate the genetic determination of NB.

Related: Neuroblastoma

Perri P, Longo L, Cusano R, et al.
Weak linkage at 4p16 to predisposition for human neuroblastoma.
Oncogene. 2002; 21(54):8356-60 [PubMed] Related Publications

The most frequent genetic alterations described in neuroblastoma (NB) are amplification of MYCN oncogene and deletion of chromosome 1p, although somatic deletions have been demonstrated at other chromosomal intervals. Since loss of heterozygosity (LOH) at distal 4p has been observed in about 20-29% of neuroblastomas, we have evaluated deletions in 41 Italian NB samples by LOH analysis at loci mapping to 4p as follows: pter-D4S2936-D4S412-D4S2957-D4S432-D4S3023-D4S431-cen. Our analysis showed allele losses in eight out of 41 samples (19.5%) and allowed the identification of a smallest region of overlapping deletion (SRO) of 3.0 cM, delimited by D4S412 and D4S3023. Two of these tumors with 4p LOH are from patients belonging to a family with recurrent NB. Interestingly the genotyping of this family revealed an identical haplotype that includes the nonrecombinant loci D4S412, D4S2957 and D4S432 shared by all affected children and demonstrated that this haplotype is retained in the two tumors carrying somatic deletions from patients of this family. Furthermore linkage analysis was performed in two NB families and yielded an overall lod-score of 3.0 in the interval including the haplotype. This provides a confirmatory indication that the region delimited by D4S2936 and D4S3023, which also includes the new defined SRO, may harbor NB predisposing gene/s.

Related: Chromosome 4 Neuroblastoma

Ankathil R, Kusumakumary P, Priyakumary T, Krishnan Nair M
Expression of folate sensitive and aphidicolin induced chromosomal fragile sites in familial neuroblastoma.
J Exp Clin Cancer Res. 2002; 21(3):383-8 [PubMed] Related Publications

The expression of folate sensitive and aphidicolin induced fragile sites in the blood lymphocyte chromosomes of affected and unaffected members from 2 neuroblastoma families were studied. The subjects included 4 neuroblastoma patients, and 9 of their clinically healthy first degree relatives and corresponding number of age and sex matched controls. Lymphocytes cultured in folate deprived culture medium showed rare fragile sites at band p13.1 of chromosome 1, in a frequency of 3%-5% in all the 4 neuroblastoma patients. In aphidicolin treated cultures, the patients and unaffected members in neuroblastoma families, showed hypersensitivity to aphidicolin, as evidenced by the significant increase in percentage of aberration/cell (ab/c) and damaged cells (dc), over that of controls (P < 0.01). Aphidicolin induced fragile sites were more pronounced in chromosomes 1 and 2. A larger number of subjects have to be studied to prove whether altered fragile site expression may be a cytogenetic evidence for an individual or familial cancer predisposing genetic constitution.

Related: Chromosome 1 Chromosome 2 Neuroblastoma

Tonini GP, McConville C, Cusano R, et al.
Exclusion of candidate genes and chromosomal regions in familial neuroblastoma.
Int J Mol Med. 2001; 7(1):85-9 [PubMed] Related Publications

Two families with recurrence of neuroblastoma one Italian and one British with three and two affected children respectively were genotyped using polymorphic markers on chromosome 1 spanning the p32-p36 region frequently deleted in neuroblastoma tumor cells. Linkage to this region was excluded by haplotype inspection and negative lod scores. Furthermore, the exclusion of genes involved in neurocristopathies sometimes associated with neuroblastoma was carried out by typing the Italian family with polymorphic markers located in or near the corresponding genes. Finally, linkage analysis in the two families showed negative lod scores for markers spanning the 16p12-13 chromosomal region where a locus for familial neuroblastoma has been recently mapped. Our findings indicate that different genes are involved in the pathogenesis of familial neuroblastoma.

Related: Neuroblastoma

Chatten J, Voorhess ML
Familial neuroblastoma. Report of a kindred with multiple disorders, including neuroblastomas in four siblings.
N Engl J Med. 1967; 277(23):1230-6 [PubMed] Related Publications

Related: Neuroblastoma

Griffin ME, Bolande RP
Familial neuroblastoma with regression and maturation to ganglioneurofibroma.
Pediatrics. 1969; 43(3):377-82 [PubMed] Related Publications

Related: Neuroblastoma

Wong KY, Hanenson IB, Lampkin BC
Familial neuroblastoma.
Am J Dis Child. 1971; 121(5):415-6 [PubMed] Related Publications

Related: Neuroblastoma

Feingold M, Gheradi GJ, Simons C
Familial neuroblastoma and trisomy 13.
Am J Dis Child. 1971; 121(5):451 [PubMed] Related Publications

Related: Neuroblastoma

Hardy PC, Nesbit ME
Familial neuroblastoma: report of a kindred with a high incidence of infantile tumors.
J Pediatr. 1972; 80(1):74-7 [PubMed] Related Publications

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Gerson JM, Chatten J, Eisman S
Letter: Familial neuroblastoma: a follow-up.
N Engl J Med. 1974; 290(26):1487 [PubMed] Related Publications

Related: Neuroblastoma

Roberts FF, Lee KR
Familial neuroblastoma presenting as multiple tumors.
Radiology. 1975; 116(1):133-6 [PubMed] Related Publications

Multiple primary tumors are a common mode of presentation in familial neuroblastoma but must be differentiated from metastatic disease. The cases of 2 siblings with multiple neuroblastomas are presented and 44 additional cases of neuroblastoma reviewed. It was found that primary tumors localize to the posterior mediastinum, the adrenals, and the paravertebral ganglia whereas metastatic disease is found in the anterior and middle mediastinum, bones and para-aortic nodes. Based on these observations, the diagnosis of multiple primary tumors can be made and should lead to early consideration of familial neuroblastoma.

Related: Neuroblastoma

Pegelow CH, Ebbin AJ, Powars D, Towner JW
Familial neuroblastoma.
J Pediatr. 1975; 87(5):763-5 [PubMed] Related Publications

Related: Neuroblastoma

Piöchl E, Käser H, Klein H
Excretion of catecholamines in relatives of patients with familial neuroblastoma.
Cancer Res. 1976; 36(1):10-12 [PubMed] Related Publications

The urinary excretion of catecholamines in 13 close relatives of two distantly related patients with congenital neuroblastoma was investigated. One of these relatives was a child with already known ganglioneuroblastoma. The catecholamines noradrenaline and dopamine were determined. Vanilmandelic acid and homovanillic acid also were determined and numerous other catecholamine metabolites were measured. In contrast to some previous reports in the literature, no pathological excretion patterns were found in the healthy family members.

Related: Neuroblastoma

Bond JV
Letter: Familial neuroblastoma and ganglioneuroma.
JAMA. 1976; 236(6):561-2 [PubMed] Related Publications

Related: Neuroblastoma

Hecht F, Hecht BK, Northrup JC, et al.
Genetics of familial neuroblastoma: long-range studies.
Cancer Genet Cytogenet. 1982; 7(3):227-30 [PubMed] Related Publications

This is a longitudinal study of a family prone to neuroblastoma. The family was originally reported in 1975 when three children in a single generation were found to be affected. We now report the case of a fourth affected child, the sole child born in the succeeding generation. Cytogenetic studies have disclosed the segregation in the family of a paracentric inversion of the long (q) arm of chromosome No. 11 and a deletion of the short (p) arm of chromosome No. 21. However, the independent assortment of the inv(11q) and 21p- chromosomes with neuroblastoma permits us to exclude them as linkage markers for the neuroblastoma gene.

Related: Neuroblastoma

Kushner BH, Gilbert F, Helson L
Familial neuroblastoma. Case reports, literature review, and etiologic considerations.
Cancer. 1986; 57(9):1887-93 [PubMed] Related Publications

The phenomenon of familial neuroblastoma is discussed in the context of case reports describing disseminated neuroblastoma in two of three half-brothers who share a common unaffected mother and who each have a different father. This family's cytogenetics proved to be unremarkable; also, the mother's peripheral blood DNA did not show tumorigenic capacities in transfection-nude mice experiments. An analysis of reported cases permits an updated examination of the clinical features of this entity and defines the limits of genetic counseling of families of all neuroblastoma patients. Multiple primaries are a hallmark of familial neuroblastoma. Most diagnoses are made in the first 18 months of life and at ages that fall within 12 months of the age of diagnosis of the other affected family member. Difficulties in determining the incidence and penetrance of an inherited susceptibility to neuroblastoma derive from undiagnosed tumors that have undergone regression or spontaneous maturation to benign ganglioneuroma, as well as from early deaths or long-term treatment complications that preclude reproduction and multigenerational pedigrees. Nevertheless, the risk of neuroblastoma in siblings or offspring of the large majority of persons with neuroblastoma appears to be less than 6%. Recent observations concerning chromosomal aberrations and oncogenes in embryonal malignancies are presented in an integrated model of tumorigenesis that corresponds to clinical experience.

Related: Neuroblastoma

Maris JM, Chatten J, Meadows AT, et al.
Familial neuroblastoma: a three-generation pedigree and a further association with Hirschsprung disease.
Med Pediatr Oncol. 1997; 28(1):1-5 [PubMed] Related Publications

Like the other embryonal cancers of childhood, neuroblastoma occasionally occurs within families. We now provide an update on a nuclear family in which seven individuals are affected with neuroblastoma, inherited in an autosomal dominant fashion over three generations. In addition, two of these individuals are also affected with Hirschsprung disease. This family may lend insight into the molecular pathogenesis of familial neuroblastoma.

Related: Neuroblastoma

Altura RA, Maris JM, Li H, et al.
Novel regions of chromosomal loss in familial neuroblastoma by comparative genomic hybridization.
Genes Chromosomes Cancer. 1997; 19(3):176-84 [PubMed] Related Publications

Childhood neuroblastoma, an embryonal neoplasm of sympathetic nervous system progenitors, occurs in a familial form with an autosomal dominant mode of inheritance. Genetic susceptibility to this disorder is thought to arise via a germline mutation affecting a tumor suppressor gene, in accord with the two-hit model established for familial and sporadic retinoblastoma. Surprisingly, the familial neuroblastoma predisposition locus does not map to chromosome band 1p36, a genomic region likely to contain one or more neuroblastoma suppressor genes. We reasoned that inherited point mutations affecting one allele would be unmasked in many cases by somatically acquired deletions of the second allele that included the target gene in the tumor cells from these patients. Thus, to identify chromosomal regions that might contain suppressor genes important in hereditary neuroblastoma, we analyzed six familial tumors by comparative genomic hybridization. Recurrent losses of genetic material were detected on chromosome arms 3p (consensus region, 3p24-pter), 10p (consensus, 10p12-p13), 10q (consensus, 10q25-qter), 16q (consensus, 16q12-q22), and 20q (consensus, 20q13.3-qter), in addition to the regions commonly deleted in sporadic neuroblastomas (1p36 and 11q). These chromosomal sites may harbor novel tumor suppressor genes that could aid in our understanding of the predisposition to and pathogenesis of familial neuroblastoma and potentially sporadic tumors as well.

Related: FISH Neuroblastoma

Maris JM, Kyemba SM, Rebbeck TR, et al.
Molecular genetic analysis of familial neuroblastoma.
Eur J Cancer. 1997; 33(12):1923-8 [PubMed] Related Publications

Neuroblastoma has several clinical and molecular genetic parallels with the other paediatric embryonal tumours, such as retinoblastoma, including a hereditary form of the disease. We hypothesised that neuroblastoma susceptibility is due to germline mutations in a tumour suppressor gene and that this predisposition gene may be involved in sporadic neuroblastoma tumorigenesis as well. We therefore aimed to localise the familial neuroblastoma predisposition gene by linkage analysis in neuroblastoma kindreds. Eighteen families segregating for neuroblastoma were ascertained for candidate locus linkage analysis. Although many of the 49 affected individuals in these families were diagnosed as infants with multifocal primary tumours, there was marked clinical heterogeneity. We originally hypothesised that familial neuroblastoma predisposition would map to the telomeric portion of chromosome band 1p36, a genomic region likely to contain a sporadic neuroblastoma suppressor gene. However, neuroblastoma predisposition did not map to any of eight polymorphic markers spanning 1p36.2-.3 in three large kindreds. In addition, there was strong evidence against linkage to two Hirschsprung disease susceptibility genes (RET and EDNRB), a condition that can cosegregate with neuroblastoma as in one of the kindreds tested here. We conclude that the neuroblastoma susceptibility gene is distinct from the 1p36 neuroblastoma suppressor and two of the currently identified Hirschsprung disease susceptibility genes.

Related: Chromosome 1 Chromosome 10 Chromosome 13 Neuroblastoma

Perri P, Pession A, Mazzocco K, et al.
Restriction fragment length polymorphism analysis reveals different allele frequency and a linkage disequilibrium at locus D1S94 in neuroblastoma patients.
Eur J Cancer. 1997; 33(12):1949-52 [PubMed] Related Publications

Deletion of chromosome 1p and MYCN amplification have been reported as frequent abnormalities in human neuroblastoma. We studied loss of heterozygosity (LOH) in 50 (48 informative) Italian neuroblastoma patients by restriction fragment length polymorphisms (RFLPs) analysis using anonymous and hypervariable region (HVR) sequences. Twelve cases (25%) showed LOH at one or more loci. Locus D1S94 was the most frequently involved in LOH events (8/12) of deleted cases (66.6%). MYCN amplification was observed in 20% of patients which showed a significantly lower event-free survival probability (EFSp) (P = 0.004). We also studied the allelic distribution in the constitutional DNA of neuroblastoma patients (n = 44) and a matched group of healthy Italian subjects (n = 79) for loci D1S112 and D1S94. A significantly (P = 0.01) different allele frequency was detected for the two groups at locus D1S94, but not at D1S112. Moreover, the neuroblastoma population did not confirm the Hardy-Weinberg expectations at the former locus. This observation suggests the existence of an allelotype associated with neuroblastoma susceptibility.

Related: Chromosome 1 Neuroblastoma

Tonini GP, Lo Cunsolo C, Cusano R, et al.
Loss of heterozygosity for chromosome 1p in familial neuroblastoma.
Eur J Cancer. 1997; 33(12):1953-6 [PubMed] Related Publications

Loss of heterozygosity (LOH) and deletion of chromosome 1p are very often found in sporadic neuroblastoma. Nevertheless, very few data are available concerning 1p LOH in familial neuroblastoma. Families with recurrent neuroblastoma are rare and analysis of chromosome 1p in these families might give useful information for identifying the putative neuroblastoma suppressor gene. We used combined cytogenetic and molecular techniques to study 1p LOH in two neuroblastoma families. Family M has 2 out of 3 children with neuroblastoma and family C has 2 children, 1 of whom has neuroblastoma and type 1 neurofibromatosis (NF1). All patients of both families showed tumour cells with chromosome 1p deletion (1pdel), but only the patient from family C also had MYCN gene amplification. In all cases the deleted chromosome 1 was of maternal origin.

Related: Chromosome 1 FISH Neuroblastoma

Lemire EG, Chodirker BN, Williams GJ, et al.
Familial neuroblastoma: report of a kindred with later age at diagnosis.
J Pediatr Hematol Oncol. 1998 Sep-Oct; 20(5):489-93 [PubMed] Related Publications

PURPOSE: To describe the clinical and biologic features of neuroblastoma (NB) in two siblings and their maternal second cousin.
PATIENTS AND METHODS: NB was diagnosed in the siblings at 2 1/2 (patient 2) and 5 (patient 3) years of age. NB was diagnosed in their maternal second cousin (patient 1) when she was 7 years old. Standard clinical and biological data, tumor karyotype, and tumor allelotype at select loci were obtained.
RESULTS: Patient 1 had International Neuroblastoma Staging System (INSS) stage 4 NB and unfavorable histology but no evidence of MYCN amplification; she died from complications of autologous bone marrow transplantation in second remission. Patient 2 had INSS stage 4 NB with unfavorable histology but no MYCN amplification; her disease recurred 39 months after completing therapy. Patient 3 had INSS stage 1 NB with favorable biologic features; he was treated with surgical excision and remains free of disease.
CONCLUSIONS: Familial NB may occur at a later age than predicted by the tumor suppressor gene model of inherited cancer. This report further emphasizes the clinical and biological heterogeneity of familial NB.

Related: Neuroblastoma

Kusumakumary P, Ankathil R, Priyakumari T, Nair K
Familial neuroblastoma.
Indian Pediatr. 2000; 37(1):85-8 [PubMed] Related Publications

Related: Neuroblastoma

Weiss MJ, Guo C, Shusterman S, et al.
Localization of a hereditary neuroblastoma predisposition gene to 16p12-p13.
Med Pediatr Oncol. 2000; 35(6):526-30 [PubMed] Related Publications

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.

Related: Chromosome 16 Neuroblastoma

Furuta S, Ohira M, Machida T, et al.
Analysis of loss of heterozygosity at 16p12-p13 (familial neuroblastoma locus) in 470 neuroblastomas including both sporadic and mass screening tumors.
Med Pediatr Oncol. 2000; 35(6):531-3 [PubMed] Related Publications

BACKGROUND: Neuroblastoma (NBL) in children usually occurs in a sporadic form. However, it rarely occurs in families. Recently, the familial neuroblastoma (FNB) locus has been mapped to 16p12-p13 by linkage analysis.
PROCEDURE: Here we show the result of loss of heterozygosity in the region spanning 16p12-p13 (D16S406-D16S409, 46 cM) in 470 NBLs including both sporadic and mass screening cases.
RESULTS: Allelic loss was found in 61(13%) tumors. Deletion of 16p was associated with mass screening tumor (P = 0.035) and <1 year of age at diagnosis (P = 0.048). We found two commonly deleted regions: the sizes of the region were approximately 2 cM and approximately 6 cM.
CONCLUSIONS: Our data suggested that allelic loss of 16p was common in favorable NBLs, and there may be at least two candidate loci within the region of FNB.

Related: Chromosome 16 Neuroblastoma Neuroblastoma Screening Neuroblastoma - Molecular Biology

Bourdeaut F, Trochet D, Janoueix-Lerosey I, et al.
Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma.
Cancer Lett. 2005; 228(1-2):51-8 [PubMed] Related Publications

Hereditary predisposition to neuroblastoma accounts for less than 5% of neuroblastomas and is probably heterogeneous. Recently, a predisposition gene has been mapped to 16p12-p13, but has not yet been identified. Occurrence of neuroblastoma in association with congenital central hypoventilation and Hirschsprung's disease suggests that genes, involved in the development of neural-crest-derived cells, may be altered in these conditions. The recent identification of PHOX2B as the major disease-causing gene in congenital central hypoventilation prompted us to test it as a candidate gene in familial neuroblastoma. We report a family with three first-degree relatives with neuroblastic tumours (namely two ganglioneuromas and one neuroblastoma) in one branch and two siblings with Hirschsprung's disease in another branch. A constitutional R100L PHOX2B mutation was identified in all three patients affected with tumours. We also report a germline PHOX2B mutation in one patient treated for Hirschsprung's disease who subsequently developed a multifocal neuroblastoma in infancy. Both mutations disrupt the homeodomain of the PHOX2B protein. No loss of heterozygosity at the PHOX2B locus was observed in the tumour, suggesting that haplo-insufficiency, gain of function or dominant negative effects may account for the oncogenic effects of these mutations. These observations identify PHOX2B as the first predisposing gene to hereditary neuroblastic tumours.

Related: Neuroblastoma PHOX2B

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