Neuroblastoma (NB) due to a heritable mutation is predicted from the two mutation model of tumorigenesis, but the prevalence of familial NB is difficult to estimate due to clinical heterogeneity. We are attempting to define the genetic basis of familial NB through linkage and loss of heterozygosity (LOH) analyses using prioritized candidate locus approach. Ten families have been ascertained with a clear autosomal dominant pattern of inherited NB. We initially hypothesized that the predisposition gene would map to chromosome 1p36, the most common site of chromosomal deletion in sporadic NB. We analyzed 3 large families segregating for NB (13 affected individuals; 10 available for analysis) with a panel of 1p36 polymorphisms (D1S243, D1S468, D1S214, D1S1646, D1S160, D1S548,D1S489, and D1S507) covering 38 centiMorgans and spanning the consensus region of deletion. Both maximum likelihood (LOD score) and affected pedigree member (APM) linkage analyses were performed. There was no evidence to support linkage by either statistical model and there was strong evidence against linkage observed at D1S214 (LOD = -4.924). Evidence against linkage was further corroborated by the APM statistic at all loci. Furthermore, 6 individuals had matched tumor constitutional DNA specimens available. 1p LOH was not observed at any of the polymorphic loci, most of which were informative. We conclude either that the familial NB gene does not map to 1p36 or that there is genetic heterogeneity. We are extending these genetic analyses to additional families segregating for NB at 1p36 as well as to other candidate loci.
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