Neuroblastoma is a common pediatric malignancy that remains responsible for significant childhood cancer morbidity and mortality. Loss of heterozygosity (LOH) at chromosome band 1p36 occurs in up to one-third of primary neuroblastomas and a putative tumor suppressor gene has been mapped to subbands 1p36.2-3. However, the clinical significance of this rearrangement remains elusive, as all previous studies have been performed with a heterogenous sample of neuroblastomas treated in a non- uniform fashion over an extended time period. We hypothesize that 1p36 LOH independently predicts for relapse in patients whose tumors do not have MYCN amplification. First, we will determine the exact prevalence of 1p36 LOH in 300 neuroblastomas derived from a representative sample of patients from the most recent concurrent Children's Cancer Group phase III clinical trials. In addition, for all tumors with 1p LOH, we will map the extent of deletion and determine the parental origin of allelic loss to evaluate for evidence of genomic imprinting at this locus. Second, we will determine the clinical significance of 1p36 LOH. We plan to confirm our previous observation that 1p36 LOH is strongly associated with high-risk prognostic features. We will then determine the independent predictive power of 1p36 LOH to effect event-free and overall survival probability in stratified and multivariate analyses. Third, we will determine the prevalence and clinical significance of allelic loss at chromosome arms 11q and 14q, two other sites of frequent allelic loss that may harbor additional neuroblastoma suppressor genes. We will then correlate the 11q and 14q allelic status with known prognostic variables and survival. We have developed a fluorescence- based, semi-automated LOH detection system that will allow for simultaneous assessment of 15 separate polymorphic loci in a single experiment. Therefore, we anticipate efficient data collection and have made stringent plans to unambiguously assign LOH status for each locus. We expect that these studies will contribute significantly towards improving risk group assessment for neuroblastoma patients. This may lead to improvements in treatment stratification and allow for more specific therapy based upon tumor biology. These studies should also substantially contribute towards the positional cloning of three neuroblastoma suppressor genes and our basic understanding of the molecular genetics of this common pediatric tumor.
