Age associated increase in the prevalence of chromosome 22q loss of heterozygosity in histological subsets of benign meningioma

Abstract

Chromosome 22q loss of heterozygosity (LOH) is the most common allelic loss in benign meningioma and is thought to be the earliest initiating event in meningioma formation. We used published data and logistic regression to evaluate the association of 22q LOH with age at diagnosis in 318 transitional, fibroblastic, and meningothelial meningiomas. After adjustment for anatomical location, the odds ratio of 22q LOH per year of age was >1 in each histological type of meningioma, and was significantly >1 in transitional and fibroblastic meningioma. This finding is compatible with involvement of the neurofibromatosis 2 tumour suppressor gene, NF2, on chromosome 22q in the high incidence of benign meningioma in the elderly.

Meningioma is the second most common central nervous system tumour in adults. In one population based study, the age adjusted annual incidence of meningioma (intracranial and spinal tumours combined) was 4.7 per 100 000 in women and 2.0 per 100 000 in men.¹ The incidence is much higher in studies of the elderly that include asymptomatic meningioma.² The overall 5 year survival rate of patients with benign meningioma is 70%; the survival rate is higher in patients with skull base meningiomas and in younger patients.³

In addition to meningiomas that occur sporadically, meningiomas occur in about half of patients with neurofibromatosis 2 (NF2), a rare autosomal dominant disease that is caused by constitutional heterozygous inactivating mutations of the NF2 tumour suppressor gene on chromosome 22q.⁴,⁵ Somatic NF2 mutations are found in about half of sporadic meningioma.⁶,⁷,⁸ There are several differences between NF2 associated meningioma and sporadic meningioma. Multiple meningiomas are common in NF2. NF2 associated meningiomas usually occur at younger ages than sporadic meningiomas, and NF2 associated meningiomas usually have transitional or fibroblastic histology rather than meningothelial histology.

The complex processes of meningioma tumorigenesis and progression have been reviewed recently.⁹ The most common allelic loss in benign meningioma is 22q loss of heterozygosity (LOH), which occurs in about half of such tumours.⁷,¹⁰,¹¹,¹²,¹³ LOH of 22q is thought to be the earliest initiating event in meningioma formation, while allelic losses at other loci such as 1p and 14q are associated with progression from benign meningioma to atypia and anaplasia.⁹,¹⁴

In this study, we used published data and logistic regression to evaluate the association of 22q LOH with age at diagnosis in histological subsets of benign meningioma. After adjustment for anatomical location, the odds ratio of 22q LOH per year of age was >1 in each histological type of meningioma (transitional, fibroblastic, and meningothelial), and was significantly >1 in transitional and fibroblastic meningioma. This result is compatible with involvement of the NF2 gene in the high incidence of benign meningioma in the elderly.

METHODS

Published studies of 22q LOH in benign/WHO grade I meningiomas with transitional, fibroblastic, or meningothelial histology were identified through PubMed and the International NF2 Mutation Database.¹⁵ Studies were included in the analysis if microsatellite marker based methods were used to determine 22q LOH. Individual tumours were included in the analysis if there were data on histology and the patient's age at diagnosis; a subset of tumours had information on anatomical location. The literature was cross indexed to exclude multiple reports of the same tumour. The sporadic nature of the tumours was specified in most of the published studies. Additionally, as the penetrance of NF2 associated disease features increases with increasing age, meningiomas that were diagnosed at ages <20 years were excluded because of possible association with undiagnosed NF2.

In total, 318 meningiomas from 10 studies met these criteria (Wellenreuther et al,⁷ n = 49; Ruttledge et al,⁸ n = 21; Dumanski et al,¹⁰ n = 65; Leone et al,¹¹ n = 42; Kros et al,¹² n = 34; Lekanne Deprez et al,¹³ n = 39; Weber et al,¹⁴ n = 19; Papi et al,¹⁶ n = 9; Ng et al,¹⁷ n = 20; and Kim et al,¹⁸ n = 20). The studies used different sets of microsatellite markers, but in four of the largest studies, the prevalence of 22q LOH was highest in fibroblastic meningiomas and lowest in meningothelial meningiomas.⁷,¹⁰,¹¹,¹²

Statistical analysis

The χ² test and Fisher's exact test were used for univariate analyses. Logistic regression was used to evaluate the association between presence or absence of 22q LOH and the covariates of age at diagnosis and anatomical location using data from the 177 tumours that had information on anatomical location. Separate models were computed for each histological type of meningioma. Anatomical location was coded as a binary variable (non‐skull base or skull base). Associations were evaluated using odds ratios (OR) of 22q LOH and their 95% confidence intervals (CI) from the logistic regression models.

RESULTS

The characteristics of the tumours are presented in table 1. The median age at diagnosis was 58 years (range 20 to 87). The sex ratio (3.4:1 female:male) was similar to the sex ratio for meningioma in the general population.¹ The prevalence of 22q LOH was higher in men (51 of 72 tumours, 71%) than in women (143 of 246 tumours, 58%) (Fisher's exact test, p = 0.055). As expected, the distribution of histological types varied by anatomical location. Among the 177 tumours with information on anatomical location, 29 (30%) of 96 transitional meningiomas were in the skull base, compared with four (13%) of 31 fibroblastic meningiomas and 21 (42%) of 50 meningothelial meningiomas (χ² test, p = 0.022, table 2).

Table 1 Characteristics of 318 benign meningiomas.

Characteristic		n		%
Gender
Female		246		77
Male		72		23
Age at diagnosis (years)
<60		169		53
⩾60		149		47
Histology
Transitional		140		44
Fibroblastic		71		22
Meningothelial		107		34
Anatomical location
Non‐skull base		123		69
Skull base		54		31

60 years of age was used as the cutoff point because the median age at diagnosis of meningioma was 58 years. n = 177 for anatomical location. The specific locations of non‐skull base meningiomas were 99 tumours in the convexity, nine tumours in the spine, seven tumours in the posterior fossa, seven tumours in the falx, and one tumour in the orbit.

Table 2 Univariate analyses of histology, age at diagnosis, and anatomical location of 318 benign meningiomas in relation to presence or absence of 22q LOH.

Histology, age at diagnosis, and anatomical location		22q LOH				p
		−		+
Transitional
Age at diagnosis (years)						0.059
<60		36		40
⩾60		20		44
Anatomical location						0 .045
Non‐skull base		28		39
Skull base		19		10
Fibroblastic
Age at diagnosis (years)						0.019
<60		9		30
⩾60		1		31
Anatomical location						1.000
Non‐skull base		1		26
Skull base		0		4
Meningothelial
Age at diagnosis (years)						0.335
<60		32		22
⩾60		26		27
Anatomical location						0.003
Non‐skull base		12		17
Skull base		18		3

60 years of age was used as the cutoff point because the median age at diagnosis of meningioma was 58 years. n = 177 for anatomical location.

Overall, 22q LOH was present in 194 (61%) of the 318 meningiomas, but there were notable differences between and within histological types (table 2). LOH of 22q was present in 84 (60%) of 140 transitional meningiomas, 61 (86%) of 71 fibroblastic meningiomas, and 49 (46%) of 107 meningothelial meningiomas (χ² test, p<0.001). Among meningothelial meningiomas, 22q LOH was present in 17 (59%) of 29 tumours in non‐skull base locations, but in only three (14%) of 21 tumours in the skull base (Fisher's exact test, p = 0.003).

The prevalence of 22q LOH increased with increasing age at diagnosis in each histological type of meningioma, significantly so in transitional and fibroblastic meningioma (table 2). In transitional meningioma, the prevalence of 22q LOH was 69% in older people and 53% in younger people (Fisher's exact test, p = 0.059). In fibroblastic meningioma, the prevalence of 22q LOH was 97% in older people and 77% in younger people (Fisher's exact test, p = 0.019).

The results of the logistic regression models are presented in table 3. After adjustment for anatomical location, the OR of 22q LOH per year of age was >1 in each histological type of meningioma, and was significantly >1 in transitional and fibroblastic meningioma. The point estimates for the OR of 22q LOH per year of age were 1.04 in transitional meningioma, 1.09 in fibroblastic meningioma, and 1.03 in meningothelial meningioma

Table 3 Logistic regression models for histological subsets of meningioma with presence or absence of 22q LOH as the outcome.

Histological type and covariates		OR		95% CI
Transitional
Age at diagnosis (per year)		1.04		1.01 to 1.07
Anatomical location
Non‐skull base		1.00*
Skull base		0.95		0.81 to 1.11
Fibroblastic†
Age at diagnosis (per year)		1.09		1.01 to 1.17
Meningothelial
Age at diagnosis (per year)		1.03		0.99 to 1.08
Anatomical location
Non‐skull base		1.00*
Skull base		0.09		0.02 to 0.41

This table summarises the results of three logistic regression models, one for each histological type of meningioma. Gender did not contribute significantly to any of the models and there were not significant interactions between age at diagnosis and anatomical location. *Reference group; †anatomical location was not included as a covariate for fibroblastic meningioma because there were only four fibroblastic meningiomas in the skull base. OR, odds ratio; CI, confidence interval.

DISCUSSION

This is the largest study to date of 22q LOH in benign meningioma and the first to evaluate the association of 22q LOH with age at diagnosis in histological subsets of benign meningioma. The age associated increase in the prevalence of 22q LOH in each histological type of meningioma is compatible with involvement of the NF2 gene in the high incidence of meningioma in the elderly. The increased prevalence of 22q LOH could be due to increasing genomic instability or deficient DNA repair. Genomic instability in meningioma (as indicated by number of chromosomes) does not increase significantly with increasing age.¹⁹ This suggests that deficient DNA repair may be the most likely explanation; additional studies of allelic loss in normal meningeal tissue from older people may be useful in addressing this question.²⁰

Somatic NF2 mutations and 22q LOH are more common in transitional and fibroblastic meningioma than in meningothelial meningioma.⁷,¹²,²¹ Somatic NF2 mutations cause loss of expression of the NF2 protein,²² which is strongly associated with 22q LOH.²³NF2 mRNA²⁴ and the NF2 protein²⁵,²⁶ are absent in transitional and fibroblastic meningioma, but are present in meningothelial meningioma.

The low prevalence of 22q LOH in skull base meningothelial meningiomas may reflect anatomical differences in initiating events among the histological subsets of meningioma. Kros et al¹² noted that the prevalence of 22q LOH was particularly low in anterior skull base meningiomas, but there was insufficient information for most of the tumours in this study to distinguish between locations in the anterior and posterior skull base.

This study focused on 22q LOH, for which there is sufficient published data for statistical analyses, but other genetic and hormonal factors have been implicated in the genesis of benign meningioma.⁹ It is likely, for example, that such factors are more important than 22q LOH in the aetiology of skull base meningothelial meningiomas, which have a very low prevalence of 22q LOH. About half of benign meningiomas do not have losses of 22q, and there are losses of 1p and 3p in some of these tumours.²⁷ Loss of protein 4.1 family gene expression and gain of progesterone receptor expression occur in benign meningioma.²⁸,²⁹,³⁰ In addition to NF2, other genes on 22q may be involved in meningiomagenesis, for example, BAM22,³¹MN1,³² and IN11.³³ Further research is needed to identify the various genes that are involved in the genesis of the different histological types of benign meningioma.