Mononucleotide repeat instability is infrequent in neuroblastoma

Neuroblastoma is a pediatric malignancy of the sympathetic nervous system and is frequently characterized by genetic aberrations (including aneuploidy, chromosomal deletions, translocations, and gene amplification) that suggest inherent genomic instability. Mutations in mismatch repair (MMR) genes have been associated with genomic instability in several human cancers, such as those of the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. In these cases, replication errors at microsatellite repeats lead to microsatellite instability (MSI) and mutagenesis. In neuroblastoma, we and others have detected MSI infrequently when analyzed at di- or tetranucleotide repeat polymorphic markers. More recently, however, mutations in the MMR gene GTBP/hMSH6 have been associated with a limited phenotype of instability at mononucleotide repeats only (e.g., polyadenine tracts). Furthermore, mononucleotide repeats appear to be common downstream targets of MSI-related mutagenesis and are present in the transforming growth factor-β receptor-II gene (TGFβRII), the BAX proapoptosis gene, and the insulin-like growth factor II receptor gene (IGFIIR) frequently in tumors arising in HNPCC kindreds. Therefore, we analyzed 46 matched normal and tumor DNAs representing all clinical stages of neuroblastoma with the use of five polymorphic mononucleotide repeat markers to assess for MSI at mononucleotide repeats. Only one tumor (2%) demonstrated mononucleotide repeat instability, and the instability was at a single locus. We conclude that MSI, including mononucleotide repeat instability, is infrequent in human neuroblastoma, and therefore defects in DNA mismatch repair are not responsible for the genomic instability seen in this neoplasm.