Alterations of the INK4a/ARF locus in human intracranial germ cell tumors

Little is known about the molecular mechanisms responsible for the developm ent of intracranial germ cell tumors (ICGTs), Recently, we demonstrated tha t the balance of the p53-mdm2 interactions is disrupted in ICGTs, The p14(A RF) product, a tumor suppresser gene located on the INK4a/ARF locus, acts a s one of the major factors affecting p53-mdm2 interactions via its binding to mdm2 and the stimulation of mdma degradation. To evaluate whether geneti c alterations of the INK4a/ARF locus occur in the genesis of ICGTs, we anal yzed the INK4a/ARF genes in 21 ICGTs-10 pure germinomas and 11 nongerminoma tous germ cell tumors. Fifteen (71%) of the 21 ICGTs displayed genetic alte rations, including 14 homozygous deletions and 1 frameshift mutation. Furth ermore, the frequency of the alterations was higher in pure germinomas [9 ( 90%) of the 10] than in nongerminomatous germ cell tumors [6 (55%) of the 1 1; P = 0.09], These data suggested that INK4a/ARF gene abnormalities could play an important role in the genesis of ICGTs, especially in pure germinom a.