Weak linkage at 4p16 to predisposition for human neuroblastoma.

The most frequent genetic alterations described in neuroblastoma (NB) are amplification of MYCN oncogene and deletion of chromosome 1p, although somatic deletions have been demonstrated at other chromosomal intervals. Since loss of heterozygosity (LOH) at distal 4p has been observed in about 20-29% of neuroblastomas, we have evaluated deletions in 41 Italian NB samples by LOH analysis at loci mapping to 4p as follows: pter-D4S2936-D4S412-D4S2957-D4S432-D4S3023-D4S431-cen. Our analysis showed allele losses in eight out of 41 samples (19.5%) and allowed the identification of a smallest region of overlapping deletion (SRO) of 3.0 cM, delimited by D4S412 and D4S3023. Two of these tumors with 4p LOH are from patients belonging to a family with recurrent NB. Interestingly the genotyping of this family revealed an identical haplotype that includes the nonrecombinant loci D4S412, D4S2957 and D4S432 shared by all affected children and demonstrated that this haplotype is retained in the two tumors carrying somatic deletions from patients of this family. Furthermore linkage analysis was performed in two NB families and yielded an overall lod-score of 3.0 in the interval including the haplotype. This provides a confirmatory indication that the region delimited by D4S2936 and D4S3023, which also includes the new defined SRO, may harbor NB predisposing gene/s.

Linkage analysis in families with recurrent neuroblastoma.

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.