MONONUCLEOTIDE REPEAT INSTABILITY IS INFREQUENT IN NEUROBLASTOMA

Neuroblastoma is a pediatric malignancy of the sympathetic nervous sys tem and is frequently characterized by genetic aberrations (including aneuploidy, chromosomal deletions, translocations, and gene amplificat ion) that suggest inherent genomic instability Mutations in mismatch r epair (MMR) genes have been associated with genomic instability in sev eral human cancers, such as those of the hereditary nonpolyposis color ectal cancer (HNPCC) syndrome. In these cases, replication errors at m icrosatellite repeats lead to microsatellite instability (MSI) and mut agenesis. In neuroblastoma, we and others have detected MSI infrequent ly when analyzed at di- or tetranucleotide repeat polymorphic markers, More recently, however, mutations in the MMR gene GTBP/hMSH6 have bee n associated with a limited phenotype of instability at mononucleotide repeats only (e.g., polyadenine tracts). Furthermore, mononucleotide repeals appear to be common downstream targets of MSI-related mutagene sis and are present in the transforming growth factor-beta receptor-II gene (TGF beta RII), the BAX proapoptosis gene, and the insulin-like growth factor II receptor gene (IGFIIR) frequently in tumors arising i n HNPCC kindreds. Therefore, we analyzed 46 matched normal and tumor D NAs representing all clinical stages of neuroblastoma with the use of five polymorphic mononucleotide repeat markers to assess for MSI at mo nonucleotide repeats. Only one tumor (2%) demonstrated mononucleotide repeat instability, and the instability was at a single locus. We conc lude that MSI, including mononucleotide repeat instability, is infrequ ent in human neuroblastoma, and therefore defects in DNA mismatch repa ir are not responsible for the genomic instability seen in this neopla sm. (C) Elsevier Science Inc., 1998.