DELETION MAP OF CHROMOSOME-9 AND P16 (CDKN2A) GENE ALTERATIONS IN NEUROBLASTOMA

We reported previously that loss of heterozygosity (LOH) on chromosome s 29, 9p and 189 frequently occurs in neuroblastoma and that patients with 9p LOH in the tumors shelved statistically significant associatio n with an advanced stage of the disease and poor prognosis. To determi ne the role of chromosome 9 Loss in neuroblastoma, me performed deleti on mapping of chromosome 9 in 80 cases of neuroblastoma using 11 polym orphic microsatellite markers and a restriction fragment length porymo rphism marker. LOH at one or more loci on chromosome 9 was detected in 33 of 80 cases (41%). Chromosome 9p was Lost in 33 of 80 cases (32%), whereas chromosome 9q was lost in 18 of 80 cases (23%). There were tw o commonly deleted regions mapped to 9p21 between the D9S171 marker an d the IFNB1 marker and 9q34-qter distal to the D9S176 marker, In addit ion, patients with I,OH at 9p21 but not at 9q34-qter in the tumors sho wed statistically significant association with poor prognosis (P = 0.0 23). Because the commonly deleted regions at 9p21 includes the p16 (CD KN2A) gene, the status of the p16 gene was further examined in 80 fres h tumors and 19 cell lines of neuroblastoma. A missense mutation was d etected at codon 52 in a fresh tumor, The pld gene was not expressed i n 13 of 19 cell lines (72%), and 5 of the 13 cell lines displayed meth ylation of the CpG island surrounding the first exon of the p16 gene. These results suggest that the p16 gene is a candidate tumor suppresso r gene for neuroblastoma, and its inactivation may contribute to the p rogression of neuroblastoma.