580

BARD1

-;BRCA1 associated RING domain 1;BARD1;BRCA1 associated RING domain 1

BARD-1|BRCA1 associated RING domain 1 isoform alfa|BRCA1 associated RING domain 1 isoform beta|BRCA1 associated RING domain 1 isoform delta|BRCA1 associated RING domain 1 isoform epsilon|BRCA1 associated RING domain 1 isoform eta|BRCA1 associated RING dom

2q34-q35

protein-coding

Neuroblastoma is a pediatric cancer of the developing sympathetic nervous systemthat 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 greatlyaccording 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 totumor initiation such as rare mutations at locus 2p23 (in ALK gene) for familialneuroblastoma, common SNPs at 6p22 (FLJ22536 and FLJ44180) and 2q35 (BARD1), anda 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 genomeinteract to exact phenotypic differences in neuroblastoma, and cancer in general.

BACKGROUND: Neuroblastoma is an often fatal pediatric cancer more frequent in European-American than African-American children. African-American children, however, are at higher risk for the more severe form of neuroblastoma and have worse overall survival than European-American children. Genome-wide association studies (GWAS) have identified several single-nucleotide polymorphisms (SNP) associated to neuroblastoma in children of European descent. Knowledge of their association to neuroblastoma in African-American children is still lacking. METHODS: We genotyped and imputed SNPs located in three gene regions reported tobe associated to neuroblastoma in children of European descent, and tested them for association in 390 African-American patients with neuroblastoma compared with 2,500 healthy, ethnically matched controls. RESULTS: SNPs in the BARD1 gene region show a similar pattern of association to neuroblastoma in African-American and European-American children. The more restricted extent of linkage disequilibrium in the African-American population suggests a smaller candidate region for the putative causal variants than previously reported. Limited association was observed at the other two gene regions tested, including LMO1 in11p15 and FLJ22536 in 6p22. CONCLUSIONS: Common BARD1 SNPs affect risk of neuroblastoma in African-Americans. The role of other SNPs associated to neuroblastoma in children of European descent could not be confirmed, possibly due to different patterns of linkage disequilibrium or limited statistical powerto detect association to variants with small effect on disease risk. Extension of GWAS to populations of African descent is important to confirm their results andvalidity beyond the European populations and can help to refine the location of the putative causal variants.#CI- (c)2012 AACR.