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(American Journal of Pathology. 2001;159:661-669.)
© 2001 American Society for Investigative Pathology

Regular Articles

Alterations of the Tumor Suppressor Genes CDKN2A (p16^INK4a), p14^ARF, CDKN2B (p15^INK4b), and CDKN2C (p18^INK4c) in Atypical and Anaplastic Meningiomas

Jan Boström^*, Birgit Meyer-Puttlitz, Marietta Wolter, Britta Blaschke, Ruthild G. Weber, Peter Lichter^¶, Koichi Ichimura^||, V. Peter Collins^|| and Guido Reifenberger

From the Departments of Neurosurgery^*
and Neuropathology,
University of Bonn Medical Center, Bonn, Germany; the Department of Neuropathology,
Heinrich-Heine-University, Düsseldorf, Germany; the Institute of Human Genetics,
Ruprecht-Karls-University, Heidelberg, Germany; the Department Organization of Complex Genomes,^¶
German Cancer Research Center, Heidelberg, Germany; and the Department of Pathology,^||
Division of Molecular Histopathology, Addenbrooke’s Hospital, Cambridge, United Kingdom

We investigated 67 meningothelial tumors (20 benign meningiomas, 34 atypical meningiomas, and 13 anaplastic meningiomas) for losses of genetic information from chromosome arms 1p and 9p, as well as for deletion, mutation, and expression of the tumor suppressor genes CDKN2A (p16^INKa/MTS1), p14^ARF, CDKN2B (p15^INK4b/MTS2) (all located at 9p21) and CDKN2C (1p32). Comparative genomic hybridization and microsatellite analysis showed losses on 1p in 11 anaplastic meningiomas (85%), 23 atypical meningiomas (68%), and 5 benign meningiomas (25%). One atypical meningioma with loss of heterozygosity on 1p carried a somatic CDKN2C mutation (c.202C>T: R68X). Losses on 9p were found in five anaplastic meningiomas (38%), six atypical meningiomas (18%), and one benign meningioma (5%). Six anaplastic meningiomas (46%) and one atypical meningioma (3%) showed homozygous deletions of the CDKN2A, p14^ARF, and CDKN2B genes. Two anaplastic meningiomas carried somatic point mutations in CDKN2A (c.262G>T: E88X and c.262G>A: E88K) and p14^ARF (c.305G>T: G102V and c.305G>A: G102E). One anaplastic meningioma, three atypical meningiomas, and one benign meningioma without a demonstrated homozygous deletion or mutation of CDKN2A, p14^ARF, or CDKN2B lacked detectable transcripts from at least one of these genes. Hypermethylation of CDKN2A, p14^ARF, and CDKN2B could be demonstrated in one of these cases. Taken together, our results indicate that CDKN2C is rarely altered in meningiomas. However, the majority of anaplastic meningiomas either show homozygous deletions of CDKN2A, p14^ARF, and CDKN2B, mutations in CDKN2A and p14^ARF, or lack of expression of one or more of these genes. Thus, inactivation of the G₁/S-phase cell-cycle checkpoint is an important aberration in anaplastic meningiomas.

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