Exclusion of candidate genes and chromosomal regions in familial neuroblastoma.

Tonini, G.; McConville, Carmel; Cusano, Roberto; Rees, Sally A.; Dagnino, Monica; Longo, Luca; Bernardi, Bruno; Conte, Massimo; Garaventa, Alberto; Romeo, Giovanni; Devoto, Marcella; Seri, Marco

doi:10.3892/ijmm.7.1.85

Cited by 5 publications

(9 citation statements)

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“…3). Negative lod score values for all 13 microsatellite markers analyzed provide no evidence for linkage in family IGG‐E at the target interval28 (Table 1A). Lod score values for VNTR markers in family UB‐NB1 are not informative because of the inadequate pedigree structure.…”

Section: Resultsmentioning

confidence: 98%

Linkage Analysis in Families with Recurrent Neuroblastoma

Perri¹,

Longo²,

McConville

et al. 2002

Annals of the New York Academy of Sciences

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Neuroblastoma is a neural crest‐derived tumor of childhood with a serious prognosis; only 20% of patients with stage 4 disease survive 5 years from diagnosis. Mechanisms involved in neuroblastoma development are unclear, but the engagement of many neuroblastoma‐related gene(s) is suggested by specific chromosomal alterations. Most prominent among these is the amplification of the MYCN oncogene and the deletion of the 1p36 region. Other genetic aberrations have been discovered over the years such as deletions of 11q and 14q and gain of 17q. Although tumor aggressiveness greatly depends on the most frequent genetic abnormalities, to date no neuroblastoma‐related gene has been discovered. Neuroblastoma usually occurs sporadically, but 1.5% of all diagnosed cases show familial recurrence with an autosomal dominant inheritance and incomplete penetrance. A comparison between hereditary and sporadic neuroblastomas led Knudson and Strong to gather that the two‐hit hypothesis, proposed for retinoblastoma, could be applied to neuroblastoma. To determine if the 1p36 region harbors a predisposition gene for familial neuroblastoma, we carried out linkage analysis at 1p36 loci in two families with recurrent neuroblastoma. Similarly, we analyzed loci of chromosome 16, where a predisposition locus was recently mapped. We also analyzed markers located close to several candidate genes (RET, NF1, GDNF, GFRA1, EDNRB, and EDN3) involved to a different extent in other neurocristopathies. Our findings indicate that the candidate chromosomal regions and genes analyzed are not in linkage with neuroblastoma.

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Section: Resultsmentioning

confidence: 98%

Linkage Analysis in Families with Recurrent Neuroblastoma

Perri¹,

Longo²,

McConville

et al. 2002

Annals of the New York Academy of Sciences

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“…Following the 'two-hit hypothesis' of inherited predisposition to the disease [7] , the 1p36 region, frequently impaired by somatic deletions in tumor samples, and some genes (NF1 , RET , GDNF , GDNFRA , EDNRB , EDN3) involved in other neurocristopathies like NF1 and HSCR were first investigated by linkage analysis with negative results [8,9] . Linkage of NB to 16p12-p13 was demonstrated in North American families [10] , whereas this region was excluded [11] and linkage to 4p16 was suggested in European families, including the family which is the subject of this study [12] .…”

Section: Introductionmentioning

confidence: 99%

Genetic Predisposition to Familial Neuroblastoma: Identification of Two Novel Genomic Regions at 2p and 12p

et al. 2007

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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.

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“…Chromosome 17q gain has been found in about 70% [22,23] and 12q gain in 25% of neuroblastoma [24]. Deletion of chromosome 4p [21], 9p [25][26][27], 11q [28][29][30], and 14q [31,32] have been observed with frequencies ranging from 20 to 30%.…”

Section: Additional Genetic Abnormalities May Provide Future Indicatimentioning

confidence: 99%

“…Remarkably, linkage analysis of neuroblastoma pedigrees argue against the presence of any disease associated gene in chromosome 1p36 region [19][20][21].…”

Section: Additional Genetic Abnormalities May Provide Future Indicatimentioning

confidence: 99%

Molecularly Guided Therapy of Neuroblastoma: A Review of Different Approaches

Tonini¹,

Pistoia²

2006

CPD

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Neuroblastoma (NB) is the most frequent extra-cranial solid tumor and the first cause of lethality in pre-school age children. NB accounts for 9-10% of pediatric tumors and affects more than ten thousand children a year. It originates from the sympathetic nervous system and is characterized by heterogeneous pathological and clinical presentation. Stage 4 NB represents approximately 50% of the cases and shows metastatic dissemination at onset; its prognosis is grim, with 20% of the patients surviving at 5 years from diagnosis in spite of aggressive chemotherapy with autologous hematopoietic stem cell support. Novel therapeutic strategies are urgently needed to improve the prognosis of stage 4 NB patients. Here we review the most promising approaches to NB treatment that have already reached clinical testing or have proved to be successful in preclinical models of the disease. All of these approaches are molecularly guided, since their rational development has benefited from the enormous amount of information on the biology of neuroblastoma gathered through molecular biology and genetics studies. The following topics are reviewed: MYCN oncogene amplification as parameter for therapeutic decision, minimal residual disease, immunotherapy, gene therapy, differentiation and apoptotic therapy, anti-angiogenic therapy, gene expression profiling as tool for generating novel therapeutic approaches. Although several efforts are still needed to reach a significant cure of patients with neuroblastoma, molecularly guided approaches have opened new ways to neuroblastoma treatment and can represent useful models for other cancers of either childhood or adulthood.

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Exclusion of candidate genes and chromosomal regions in familial neuroblastoma.

Cited by 5 publications

References 0 publications

Linkage Analysis in Families with Recurrent Neuroblastoma

Linkage Analysis in Families with Recurrent Neuroblastoma

Genetic Predisposition to Familial Neuroblastoma: Identification of Two Novel Genomic Regions at 2p and 12p

Molecularly Guided Therapy of Neuroblastoma: A Review of Different Approaches

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