ISOLATION OF THE NEUROBLASTOMA PREDISPOSITION GENE
Principal Investigator: John Maris
Abstract: Neuroblastoma remains an important pediatric disease that results in 15% of overall childhood cancer mortality. Several chromosomal aberrations that contribute to the malignant phenotypes are known, but the genetic events essential to initiate neuroblastoma tumorigenesis have not been discovered. We have shown that hereditary predisposition to develop neuroblastoma is genetically linked to the distal short arm of chromosome 16. In addition, we have demonstrated that hemizygous deletions of the same locus are a common somatically acquired event in sporadic neuroblastomas. Thus, we hypothesize that hereditary neuroblastoma is due to mutations in a tumor suppressor gene (HNB1) located at 16p12-13. We also predict that functional inactivation of this gene is responsible for the initiation of many nonfamilial human neuroblastomas, and perhaps other cancers. Accordingly, we propose to first localize HNB1 to within a one megabase region at 16p12-13 and identify candidates for mutation analysis. This will be accomplished using a multifaceted approach including high-density SNP genotyping, array-based comparative genomic hybridization, and gene expression profiling using oligonucleotide arrays. Second, we will identify HNB1 and characterize the spectrum of germline and somatically acquired mutations in familial and sporadic neuroblastomas. We will also survey a large panel of sporadic neuroblastoma primary tumor samples, as well as other human cancers with particular emphasis on neural crest derived tumors, for HNB1 mutations and loss of functional protein expression. Third, we will characterize HNB1 as a tumor suppressor and reintroduce wild-type HNB1 into HNB1-null neuroblastoma cell lines to determine effect on proliferation in vitro and tumorigenicity in vivo. Fourth, we will describe the phenotype of mice harboring heterozygous inactivation of one allele of the murine HNB1 homologue, with particular attention to neural crest tumor formation. Successful completion of these experiments will determine if inactivation of HNB1 is the seminal initiating event for human neuroblastomas, or if genetic heterogeneity exists. Successful completion of this project should dramatically improve our understanding of the fundamental genetic basis of neuroblastoma, and perhaps other human cancers. We also expect that this project will result in a valuable mouse model of this enigmatic pediatric disease. Ultimately, these experiments should lead to the identification of a common pathway to neuroblastoma tumorigenesis that will be an outstanding target for rationally designed therapeutics.
Funding Period: 1998-08-14 - 2009-04-30
more information: NIH RePORT
- Trans-population analysis of genetic mechanisms of ethnic disparities in neuroblastoma survivalEric R Gamazon
Section of Genetic Medicine, University of Chicago, 900 E 57th St, Rm 3220F, Chicago, IL 60637, USA
J Natl Cancer Inst 105:302-9. 2013..We sought to investigate the relationship between genetic variation and the disparities in survival observed in neuroblastoma...
- Identification of ALK as a major familial neuroblastoma predisposition geneYael P Mosse
Division of Oncology and Center for Childhood Cancer Research, Children s Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
Nature 455:930-5. 2008....
- Serial transcriptome analysis and cross-species integration identifies centromere-associated protein E as a novel neuroblastoma targetNaomi J Balamuth
Division of Oncology and Center for Childhood Cancer Research, Children s Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Cancer Res 70:2749-58. 2010....
- Prevalence and functional consequence of PHOX2B mutations in neuroblastomaE H Raabe
Division of Oncology, Children s Hospital of Philadelphia, Philadelphia, PA 19104 4318, USA
Oncogene 27:469-76. 2008..These data also suggest that the genetics of neuroblastoma initiation are complex, and highlight genes involved in normal noradrenergic development as candidate predisposition genes...
- NeuroblastomaJohn M Maris
Children s Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PA 19104 4318, USA
Lancet 369:2106-20. 2007..Finally, we discuss new approaches to treatment, including recently discovered molecular targets that might provide more effective treatment strategies with the potential for less toxicity...
- Integrative genomics identifies distinct molecular classes of neuroblastoma and shows that multiple genes are targeted by regional alterations in DNA copy numberQun Wang
Division of Oncology, Children s Hospital of Philadelphia, PA 19104 4399, USA
Cancer Res 66:6050-62. 2006..Lead positional candidates for neuroblastoma suppressor genes can be inferred from these data, but the potential multiplicity of transcripts involved has significant implications for ongoing gene discovery strategies...
- Region-specific detection of neuroblastoma loss of heterozygosity at multiple loci simultaneously using a SNP-based tag-array platformJohn M Maris
Division of Oncology, The Children s Hospital of Philadelphia, and Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
Genome Res 15:1168-76. 2005....
- Measurement and relevance of neuroblastoma DNA copy number changes in the post-genome eraYael P Mosse
Division of Oncology, Children s Hospital of Philadelphia, Abramson Pediatric Research Center 902A, 3615 Civic Center Blvd, Philadelphia, PA 19104 4318, USA
Cancer Lett 228:83-90. 2005....
- High-resolution detection and mapping of genomic DNA alterations in neuroblastomaYael P Mosse
Division of Oncology, Children s Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, 19104, USA
Genes Chromosomes Cancer 43:390-403. 2005..Taking all of this together indicates that aCGH can accurately measure CNAs in the neuroblastoma genome and facilitate gene discovery efforts by high-throughput refinement of candidate loci...
- The biologic basis for neuroblastoma heterogeneity and risk stratificationJohn M Maris
The Children s Hospital of Philadelphia, Division of Oncology, University of Pennsylvania School of Medicine, The Abramson Family Cancer Research Institute, Philadelphia, Pennsylvania, USA
Curr Opin Pediatr 17:7-13. 2005..This review will describe the genetic and biologic basis for the diverse clinical phenotypes observed in neuroblastoma patients. It will also discuss the current approach to risk classification and how this may change in the future...