Use of a genome-wide linkage screen to identify a hereditary neuroblastoma predisposition locus at chromosome 2p24–23

Abstract

10010 Background: A subset of neuroblastomas show inheritance as an autosomal dominant trait with incomplete penetrance. Familial neuroblastoma is often lethal during childhood, resulting in very few pedigrees of sufficient size for linkage analysis. Low-resolution genetic approaches have not been successful in identifying a narrow genomic region consistent with linkage, a critical first step in identifying the causal gene. Methods: We performed a genome-wide scan for linkage in eighteen neuroblastoma pedigrees at ∼6000 single nucleotide polymorphisms. Parametric and non-parametric analyses were used to identify and refine candidate regions. Candidate genes were resequenced in a panel of 15 probands using Sanger-based or 454 technology. Results: We discovered a highly significant linkage signal covering a 34 Mb region on chromosome 2p with a maximum non-parametric LOD score of 4.23 (p=0.00001), and 13/18 families screened were consistent with linkage to this locus. No other genomic region was suggestive of linkage in these families, including previously identified 4p16 and 16p12–13 loci. To further refine the 2p region, we performed parametric analyses in which we varied gene frequency and penetrance assumptions across a broad range. All analyses supported the initial inference of linkage, with a maximized LOD score of 6.37 (p=0.0000019) at rs1344063. By mapping informative recombination events, we defined a 16 Mb putative predisposition locus at 2p24–23, a region that includes the MYCN oncogene. Resequencing of an 18 Kb region surrounding the MYCN gene in probands from each linked family showed no activating mutations or novel sequence variations. Resequencing of other neurodevelopmental regulatory genes including NAG, DDX1, GDF7, and OSR1 has excluded these as neuroblastoma predisposition genes. Results of ongoing resequencing of a prioritized list of positional candidates will be reported. Conclusions: A hereditary neuroblastoma predisposition gene is located within a 16 Mb region at 2p24–23. We speculate that inactivation of this gene may also influence the development of non-familial human neuroblastomas. No significant financial relationships to disclose.