This is the largest case-control study to examine the relationship between family and personal medical history and meningioma risk. The results indicate the importance of a positive family history of meningioma and suggest that individuals with first-degree family members diagnosed at a young age are at even greater risk. Our findings confirm those suggested by earlier analyses based primarily on data drawn from Scandinavian tumor registries.11,12,18
The findings provide evidence that there exists an inherited gene (or genes) for meningioma, in addition to the already well-defined NF2
gene. These findings are important because, despite the fact that up to 1% of the adult population may harbor a meningioma,32
the total number of families with multiple members diagnosed with meningioma is relatively small (indicating, in part, a wide spectrum of phenotypic expression with respect to clinical importance and hence screening undertaken), and in most such families meningiomas are currently attributed to inherited NF2
mutations. At present, no family-based linkage studies of meningioma have been reported; our group is currently in the process of identifying families for such an analysis. Of note, data from Israel provide evidence of a genetic predisposition to radiation-associated meningioma,28
highlighting the role of inherited genetic factors as well as exposure in the development of meningioma.
A statistically significant inverse association between a number of immune conditions including allergy, asthma, and chicken pox with meningioma risk was seen. These findings confirm statistically nonsignificant but suggestive and consistent findings in previous reports with smaller samples sizes (all studies had fewer than 475 meningioma cases).2,4,30,31
In the sole study of similar size, eczema was significantly inversely related to meningioma risk (OR 0.74, 95% CI 0.60–0.91) but not overall allergy (OR 0.87, 95% CI 0.66–1.44).35
In our study, the risk of eczema was also reduced but not significantly. The reporting of allergy is heterogenous and subject to a number of biases. Our study required diagnosis by a doctor or health practitioner; the prevalence of allergies was 33% among control individuals, consistent with national rates. The mechanisms that link meningioma risk and immune factors remain unclear. One mechanism suggests that active immune systems that are highly allergic may be better able to recognize and respond to nascent foreign tumors. Other theories posit a more specific mechanism related to allergy, such as the promotion of an active immune rejection of the tumor based on activation of macrophages, mast cells, and eosinophils, which are characteristics of allergy.
Our current study suggests that immune factors may be protective of meningiomas, a finding that is consistent with that of malignant brain tumors. We speculate that individuals with a biased immune response consisting of a primarily humoral, specifically immunoglobulin E, response (characteristic of allergy) may be more capable of preventing nascent meningioma. This immunological bias, whether developed through environmental influences or genetic predisposition, may lead to a lifelong proclivity for hyperresponsiveness to antigens manifesting both as allergies to external antigens and effective tumor immunosurveillance in the brain.
A role for hormones in the risk of meningioma development has been hypothesized but remains ill defined.6
This association has been suggested by the increased incidence of meningioma in women that is particularly marked prior to menopause.33
The presence of hormone receptors on some meningiomas, a reported association between breast cancer and meningiomas,3,9,25
indications that meningiomas change in size during the luteal phase of the menstrual cycle and pregnancy, and in vitro proliferation of meningioma cell lines in culture after exposure to estrogens have been observed. We examined the association between sex-specific conditions and meningioma risk and noted some intriguing preliminary findings. In particular, female patients were more likely than female control individuals to report a personal (p = 0.12) and family (p = 0.07) history of breast cancer as well as uterine fibroids (p < 0.05) and endometriosis (p < 0.05). (The risk estimates for ovarian and endometrial cancer are also elevated, but the small numbers preclude definitive conclusions.) Whether these conditions are related or simply share similar risk factors is unclear; our consortium plans to further explore these findings in a larger sample as well as by meningioma hormone receptor subtype and exogenous hormone exposure. Interestingly, male patients were no more likely than controls to report a history of prostate cancer.
At present, the primary environmental risk factor identified for meningiomas is exposure to ionizing radiation, with reported risks 6–10 times higher than nonexposure to ionizing radiation.13,19,26,28,33
Evidence of this relationship is noted by the statistically increased risk of meningioma with a personal history of leukemia or thyroid cancer. Of note, in most of the individuals with leukemia the diagnosis was established when they were children and received radiation treatment to the head decades prior to their meningioma diagnosis, a second primary tumor known to be associated with such treatment.13