Analysis of genomic alterations in benign, atypical, and anaplastic meningiomas: toward a genetic model of meningioma progression

Abstract

Nineteen benign [World Health Organization (WHO) grade I; MI], 21 atypical (WHO grade II; MII), and 19 anaplastic (WHO grade III; MIII) sporadic meningiomas were screened for chromosomal imbalances by comparative genomic hybridization (CGH). These data were supplemented by molecular genetic analyses of selected chromosomal regions and genes. With increasing malignancy grade, a marked accumulation of genomic aberrations was observed; i.e., the numbers (mean +/- SEM) of total alterations detected per tumor were 2.9 +/- 0.7 for MI, 9.2 +/- 1.2 for MII, and 13.3 +/- 1.9 for MIII. The most frequent alteration detected in MI was loss on 22q (58%). In MII, aberrations most commonly identified were losses on 1p (76%), 22q (71%), 14q (43%), 18q (43%), 10 (38%), and 6q (33%), as well as gains on 20q (48%), 12q (43%), 15q (43%), 1q (33%), 9q (33%), and 17q (33%). In MIII, most of these alterations were found at similar frequencies. However, an increase in losses on 6q (53%), 10 (68%), and 14q (63%) was observed. In addition, 32% of MIII demonstrated loss on 9p. Homozygous deletions in the CDKN2A gene at 9p21 were found in 4 of 16 MIII (25%). Highly amplified DNA sequences were mapped to 12q13-q15 by CGH in 1 MII. Southern blot analysis of this tumor revealed amplification of CDK4 and MDM2. By CGH, DNA sequences from 17q were found to be amplified in 1 MII and 8 MIII, involving 17q23 in all cases. Despite the high frequency of chromosomal aberrations in the MII and MIII investigated, none of these tumors showed mutations in exons 5-8 of the TP53 gene. On the basis of the most common aberrations identified in the various malignancy grades, a model for the genomic alterations associated with meningioma progression is proposed.

Figure 1

Summary of selected clinical data, histopathological characteristics, and genomic alterations identified by CGH and other molecular genetic techniques in all meningioma groups investigated. m, Male; f, female; anapl, anaplastic; atyp, atypical; men, meningothelial; fib, fibrous; trans, transitional; ang, angiomatous; psam, psammomatous; secr, secretory; rec, recurrence; spin met, spinal metastasis; irr, irradiated prior to operation; mut, mutation; amp, amplification; ND, no data. High-level amplifications are given in boldface type in the section “gains detected by CGH.” ∗, Losses of 1p34–p36 determined by CGH were only included if confirmed by LOH data; ∗∗, meningiomas with brain invasion but no other signs of anaplasia.

Figure 3

Amplified DNA sequences were identified in MII and MIII and mapped to four different chromosomes by CGH. Shown are the images revealing the hybridization pattern of the tumor DNA (Left) next to the average ratio profile (Center). The value for the balanced threshold (1.0) and the highest threshold depicted are given for each profile. (Right) Southern blot analysis demonstrates that the genes found to be amplified on 12q were MDM2 and CDK4, which were amplified 9-fold as compared with the control locus ERBB3 (determined by densitometry; Lower Right).

Figure 2

Frequency of all CGH results obtained in the different meningioma groups. x axis, chromosomes 1–22, X, Y; y axis, number of cases. The bars showing upwards represent gains or amplifications on the short arms (shaded bars) or long arms (solid bars), whereas the bars pointing downwards stand for losses on the short arms (shaded bars) or long arms (solid bars) of the respective chromosomes.

Figure 4

(Left) Accumulation of genetic alterations during meningioma progression. All distinct genomic alterations detected in an individual tumor by the different methods used were added and are shown in their respective groups. (Right) Comparable increase of the Ki-67 proliferative index in MII and MIII versus MI. Beside the column of data points, the mean ± 2 SEM is given. ∗, Significant difference to values for MI (P < 0.05).

Figure 5

Proposed model of genomic alterations in meningioma progression. Gains and losses are given before the tumor grade in which they are first detected at a frequency of more than 30%. However, the changes may already have occurred in a lower grade in a smaller percentage of tumors. To illustrate this fact thin arrows are pointing toward the lower tumor grade.