Genetic Factors Influencing the Risk and Clinical Outcome of Neuroblastoma

Neuroblastoma is an embryonal malignancy of the sympathetic nervous system arising from neuroblasts. It is the most common solid tumor in children under the age of 5 and accounts for 8-10% of all childhood cancers (Brodeur & Maris, 2006). The disease occurs almost exclusively in infants and children below the age of 4, with median age of diagnosis approximately 17 months (Ries et al., 1999; London et al., 2005). Prognostic factors such as age at diagnosis, clinical stage, Shimada histology, amplification of MYCN, DNA ploidy, and molecular defects such as allelic loss of chromosome 1p and 11q in tumor cells are used for risk stratification and treatment assignment. The amplification of MYCN oncogene occurs in 20% to 25% of primary neuroblastomas and is consistently associated with poor outcome in neuroblastoma (Brodeur & Seeger, 1986). Although the overall 5-year survival of patients with neuroblastoma have improved considerably over the past decade, survival rates among children with high-risk neuroblastoma remains below 50%, despite marked intensification of chemotherapy (Baade et al., 2010). A particular hallmark of neuroblastoma is its clinical heterogeneity, where some patients experience spontaneous regression or differentiation of the tumor into benign ganglioneuroma, while others are affected by rapid and fatal tumor progression (Schwab et al., 2003). Although the disease is often diagnosed in the perinatal period, environmental or parental risk factors have not been identified consistently and the molecular basis of neuroblastoma development and progression is still poorly understood (Hamrick et al., 2001; Urayama et al., 2007; Munzer et al., 2008). Recent advances in genome-wide studies have proven to be a useful prognostic tool for identifying genetic alleles or regions that may be used as risk markers for neuroblastoma development. In recent years, a number of genetic and genomic changes have been identified in neuroblastoma tumors that are relevant to clinical progression, allowing tumors to be classified into subsets with distinct clinical behavior. Genome-wide association studies (GWAS) have described genetic factors influencing the risk and clinical outcome of neuroblastoma such as rare mutations in the ALK gene for familial neuroblastoma, common single nucleotide polymorphisms (SNPs) at 6p22 in FLJ22536 and FLJ44180, 2q35 in BARD1, 11p15.4 in LMO1, and copy number variation at 1q21.1 in NBPF23. Moreover, several regions with chromosomal alterations have been identified and many of these regions are speculated to harbor tumor suppressor genes.