Chromosome arm 11q deletion predicts for neuroblastoma outcome: A Children’s Oncology Group study

Abstract

6 Background: Chromosome arm 11q loss of heterozygosity (LOH) is a frequent occurrence in neuroblastoma. Previous studies have shown an association between 11q LOH and high-risk disease. However, these studies lacked the statistical power to conclusively analyze the prognostic impact of 11q LOH in multivariable analyses after adjusting for the currently used prognostic factors. Methods: We screened 917 primary neuroblastomas for chromosome 11 LOH with a panel of 4–8 microsatellite markers. Further mapping with up to 52 markers was performed on selected samples. The only inclusion criteria were availability of a constitutional DNA sample and outcome data. The sample set was representative of the overall neuroblastoma population. The median follow-up was 2.7 years. Results: LOH at chromosome arm 11q and unbalanced 11q LOH (loss of 11q material with retention or gain of 11p material) were present in 302 (33%) and 148 (16%) cases, respectively. The pattern of LOH for each tumor sample was consistent with the presence of a single region of deletion; all but two deletions involved 11q23. The majority of tumors with 11q LOH did not have MYCN amplification. Despite this, both 11q LOH and unbalanced 11q LOH were associated with high-risk disease (p<0.0001). Patients whose tumors showed unbalanced 11q LOH had 3-year EFS and OS of 50%±6% and 65%±5%, compared to 74%±2% (p<0.0001) and 83%±2% (p<0.0001) in those cases that did not (log-rank test). In a Cox proportional hazards model for multivariable analysis, unbalanced 11q LOH was independently prognostic for EFS after adjusting for stage 4, MYCN amplification, and Shimada histology (p=0.0068). Conclusion: Unbalanced 11q LOH is associated with aggressive neuroblastoma behavior and is independently prognostic for decreased EFS. Unbalanced 11q LOH status could be especially useful in determining whether a patient with locoregional neuroblastoma without MYCN amplification would benefit from more adjuvant chemotherapy. No significant financial relationships to disclose.