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Alterations of the INK4a/ARF Locus in Human Intracranial Germ Cell Tumors¹

Department of Neurosurgery, Kanazawa University School of Medicine, 920-8641 Kanazawa [M. I., O. T., Y. T., Y. A., M. H., J. Y., Y. H.], and Department of Neurosurgery, Fukui Prefectural Hospital, 910-8526 Fukui [H. N.], Japan

Little is known about the molecular mechanisms responsible for the development of intracranial germ cell tumors (ICGTs). Recently, we demonstrated that the balance of the p53-mdm2 interactions is disrupted in ICGTs. The p14^ARF product, a tumor suppresser gene located on the INK4a/ARF locus, acts as one of the major factors affecting p53-mdm2 interactions via its binding to mdm2 and the stimulation of mdm2 degradation. To evaluate whether genetic alterations of the INK4a/ARF locus occur in the genesis of ICGTs, we analyzed the INK4a/ARF genes in 21 ICGTs—10 pure germinomas and 11 nongerminomatous germ cell tumors. Fifteen (71%) of the 21 ICGTs displayed genetic alterations, including 14 homozygous deletions and 1 frameshift mutation. Furthermore, 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 11; P = 0.09]. These data suggested that INK4a/ARF gene abnormalities could play an important role in the genesis of ICGTs, especially in pure germinoma.

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