High-Resolution Analysis of Chromosome Arm 1p Alterations in Meningioma

doi:10.1016/S0165-4608(99)00249-6

Cancer Genetics and Cytogenetics

Volume 120, Issue 1, 1 July 2000, Pages 30-36

https://doi.org/10.1016/S0165-4608(99)00249-6 Get rights and content

Abstract

Loss of heterozygosity (LOH) for loci on chromosome arm 1p is a relatively common event in human meningioma, and this anomaly has been proposed to be associated with the development of grade II or grade III forms (atypical and anaplastic meningiomas). Nevertheless, the limited data available do not allow the establishment of the frequency and the extent of the affected 1p regions. To determine the status of chromosome 1p in meningiomas, we have performed a comprehensive analysis of LOH on 1p in 100 meningiomas using a high density of 1p-marker loci. Allelic loss was found in 35% of tumors, most corresponding to nontypical meningiomas that also displayed losses for loci on chromosome 22. Although some tumors displayed complex rearrangements leading to distinct 1p deletions, the patterns of loss indicated two main target regions: 1p36 and 1p34–p32, which represent the most frequently involved regions, whereas 1p22 and 1p21.1–1p13 regions appeared deleted in some tumors. These results suggest that there may be several putative tumor suppressor genes on 1p, the inactivation of which may be important in the pathogenesis of meningiomas, as well as in other tumor types.

Introduction

Meningiomas are the most common intracranial neoplasms in humans (13–19% of all primary brain tumors) and are considered to be histologically benign. In studies with long-term follow-up, some meningiomas show an increased tendency to recur after operation, as well as significant rates of morbidity and mortality. These cases are designated as atypical or anaplastic meningiomas, corresponding to grades II or III of malignancy, respectively 1, 2.

Genesis and progression of some meningiomas seem to fit a multistep tumor progression model, with accumulation of several genetic alterations 3, 4, 5. Inactivation of the NF2 (neurofibromatosis type 2) tumor suppressor gene located on 22q12 represents an early abnormality, probably leading to the formation of grade I meningiomas [6]. Allelic losses at other locations (that is, inactivation of other tumor suppressor genes) may contribute to tumor progression and, thus, to the development of atypical and anaplastic forms 3, 4, 5, 7, 8, 9, 10, 11, 12. Identification of tumors with potential evolution toward aggressive forms is often difficult, and there is a great interest in characterizing markers that might be of use in differential diagnosis.

Early loss of heterozygosity (LOH) analyses confirmed reports on nonrandom, cytogenetically visible deletions of chromosome 1p in meningiomas 8, 9. Loss of 1p regions might represent an alteration secondary to chromosome 22 tumor suppressor gene inactivation (NF2/others), and seem to participate in the genesis of the aggressive meningiomas, as this anomaly is found predominantly in atypical and anaplastic forms 8, 9. Previously available deletion mapping analysis for 1p in meningiomas proposed distinct locations of the putative tumor suppressor gene associated with meningioma progression: 1p34–pter and 1p32 have so far been identified as regions of common loss in this neoplasm 13, 14. According to our preliminary results, we recently proposed that several critical 1p regions might be related to the formation of nontypical meningiomas [5]. Here, we report an extensive, high-resolution analysis of 100 sporadic meningiomas with 39 markers (microsatellites/RFLP/VNTR) from chromosome arm 1p, and 3 markers from 1q. Our results show 1p deletions in 35 cases, most corresponding to grade II or grade III tumors, and demonstrate the involvement of several 1p regions in these neoplasms.

Section snippets

Tumor Specimens

Paired blood and tumor samples were obtained from 100 patients with meningiomas. All tumors were classified by histologic examination and graded according to WHO guidelines [2] as follows: 66 grade I (typical), 31 grade II (atypical), and 3 grade III (anaplastic) meningiomas. Histological evaluation of the tumor tissue revealed that all samples consisted of at least 75–80% tumor cells. Data on clinicopathological characteristics of these cases have been previously reported [5].

Results

Eighty-one meningiomas were initially evaluated for LOH using a panel of 15 markers spanning chromosome 1p (1pter-1p12), at an average resolution of 11.2 cM. Two 1q markers were also studied to verify whether losses involved 1p only or extended into the long arm as well. Loss of heterozygosity was found in 29 of the 81 tumors (36%), and a preliminary interpretation of the deletion pattern suggested 3 distinct regions of allelic loss: region 1, at 1p36 (defined by markers D1Z2-D1S77); region 2,

Discussion

Inactivation of at least one TSG on 1p seems to be associated with tumor progression of meningiomas, and represents an anomaly secondary to the chromosome 22 losses, as determined by cytogenetic and LOH studies 4, 5, 6, 8, 9, 21, 22, 23, 24, 25, 26, 27, 28, 29. In most instances, the inactivation of NF2, MN-1, or BAM22 genes, all three located at 22q, would contribute to the development of grade I meningiomas. Further alterations at 1p, 14q, chromosome 10, or others would accumulate to generate

Acknowledgements

This work was performed at I.I.B.-CSIC, and supported by grant 98/1348 from FIS, Ministerio de Sanidad. We are indebted to J. Alonso for collaboration with Genescan.

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Loss of chromosome 1p is the second most frequent chromosomal abnormality observed in meningiomas, and genes on 1p are commonly downregulated in anaplastic meningioma (Lusis et al., 2005). Fine-mapping has narrowed the target regions to 1p33–34 and 1p36 (Bello et al., 2000; Sulman et al., 2004). However, investigation of several candidate genes on 1p failed to show any consistent structural alterations (Niedermayer et al., 1997; Mendiola et al., 1999; Lomas et al., 2001).
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Meningiomas with loss of 1p have also been reported to be those with the highest risk of recurrence.9 The critical region of chromosomal loss has been narrowed to the 1p32, 1p34, and 1p36 loci.38-43 Although several genes within these regions, including p18, CDKN2C, p73, GADD45A, and EPB41, have been examined for mutations and polymorphisms, none has been detected.37,44-46
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Original articlesHigh-Resolution Analysis of Chromosome Arm 1p Alterations in Meningioma

Abstract

Introduction

Section snippets

Tumor Specimens

Results

Discussion

Acknowledgements

Neurosurg Clin North Am

Cancer Genet Cytogenet

Hum Pathol

Cancer Genet Cytogenet

Cancer Genet Cytogenet

Cancer Genet Cytogenet

Cancer Genet Cytogenet

Cancer Genet Cytogenet

Cancer Genet Cytogenet

Cell

Eur J Cancer

Cancer Genet Cytogenet

Histological Typing of Tumors of the Central Nervous System. International Histological Classification of Tumors

Allelic losses on chromosome 14, 10, and 1 in atypical and malignant meningiomasa genetic model of meningioma progression

Cancer Res

Analysis of genomic alterations in benign, atypical, and anaplastic meningiomastoward a genetic model of meningioma progression

Proc Natl Acad Sci USA

NF2 gene mutations and allelic status of 1p, 14q and 22q in sporadic meningiomas

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Original articles
High-Resolution Analysis of Chromosome Arm 1p Alterations in Meningioma