Risk Of Meningioma Research Articles

PMON223 Sellar Meningioma in Association with Fertility Treatment, A Case Report

Abstract Introduction Sex hormones play a crucial role in the development and growth of meningioma. Progesterone receptor is expressed in more than 70% of meningioma, practically in benign (WHO grade1) meningioma. It was observed that meningiomas increase in size and become more symptomatic during pregnancy. Similarly, the use of hormonal therapy, including gonadotropin-releasing hormone (GnRH) agonist, can be associated with an increased risk for meningioma. Moreover, the use of GnRH agonist can be associated with a risk of pituitary adenoma growth, which is difficult to distinguish from sellar meningioma by routine MRI scan. This case report shows a rare association of fertility hormonal treatment with sellar meningioma and the possible differential diagnosis. Case Presentation A 45-year-old obese woman with a past medical history of hypertension, prediabetes, hypothyroidism, and mild hyperprolactinemia presented to us with a 2-week history of persistent and worsening periorbital headache, associated with nausea, vomiting, and left retro-orbital pain with eye movement. She had undergone fertility treatment, intrauterine insemination (IUI), and hormonal therapy, including GnRH agonist, bromocriptine, and levothyroxine. She had a recent IUI 1 week prior to her presentation. She denied weakness, facial paresthesia, blurry/double vision, recent excessive weight gain/loss, or the use of any anticoagulation or antiplatelet medications. Her MRI brain scan without contrast revealed a 2.3×1.5×1.2 cm heterogeneous soft tissue mass involving the sella and left cavernous sinus with a slight impingement of the optic chiasm and left optic nerve. These findings were consistent with meningioma or pituitary macroadenoma. The patient denied any increase in her ring or shoe size, menstrual disturbances, loss of peripheral vision, orthostatic dizziness, or skin pigmentation.Her laboratory workup showed a serum prolactin of 33.3 ng/mL (reference value <25ng/mL), TSH of 2.11 mIU/L (reference value 0.5-5.0 mIU/L), free T4 of 1.3 ng/dL (reference value 0.7-1.9 ng/dL), IGF-1 of 250 ng/mL (reference value 90-360 ng/mL for people ages 40-54), morning ACTH of 6 pmol/L (reference value 10-60 pmol/L), and morning cortisol of <0.2 mcg/dL (reference value 5-25mcg/dL). In addition, she had a subnormal response for the cosyntropin stimulation test, which confirmed the diagnosis of secondary adrenal insufficiency. The patient was treated with replacement glucocorticoid therapy. She underwent an endonasal endoscopic transsphenoidal resection of the tumor, and its histopathological examination revealed meningioma with fibrosis and sclerosis, WHO grade 1.ConclusionGnRH agonist can stimulate the growth of meningioma and pituitary adenoma in women undergoing fertility treatment. Our case shows a rare association of GnRH use with sellar meningioma and how we should consider meningeal and pituitary tumors in the differential diagnosis of any sellar mass in women undergoing fertility treatment. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Cranial Irradiation for Childhood Cancers and Adult Risk of Meningioma

Introduction: Following cranial irradiation, there is an increased risk of developing secondary neoplasms, especially meningiomas. Despite childhood cancer survivors who have undergone cranial irradiation having an increased risk of acquiring radiation-induced meningioma (RIM), there is no widely used standard guideline for meningioma screening. Methods: At a single institution, we reviewed three adult survivors of childhood cancer who were treated for RIM between 2010 and 2020. We recorded age at diagnosis for the primary lesion, the radiation dose, age at RIM diagnosis, and tumor characteristics including treatment, pathology, and outcome. Two had had T-cell acute lymphocytic leukemia and one a rhabdomyosarcoma. The age of diagnosis of the RIM ranged from 20 to 40 years, with latencies ranging from 18 to 33 years. All lesions were classified as WHO Grade I meningiomas, and only 1 patient had a subsequent recurrence. A literature search identified articles that address RIM: a total of 684 cases were identified in 36 publications. Results: Mean radiation doses ranged from 1.4 gray to 70 gray. Mean age of diagnosis for secondary meningioma ranged from 8 to 53.4 years old, with latency periods ranging from 2.8 to 44 years. Given variability in the way that investigators have published their results, it is difficult to make a single recommendation for RIM screening. Using our experience and the literature, we devised two different screening protocols and calculated their expense. Conclusions: We recommend that data be standardized in a registry to provide greater insight into the clinical and resource allocation questions, especially as long-term survival of children with pediatric cancer into full adulthood becomes more commonplace worldwide.

Pooled Analysis of Meningioma Risk Following Treatment for Childhood Cancer

Meningioma is the most common subsequent neoplasm following cranial irradiation among survivors of childhood cancer, but there are still uncertainties regarding the magnitude of the radiation dose-response association, potential modifiers of radiation risks, and the role of chemotherapy. To evaluate meningioma risk in survivors of childhood cancer following radiotherapy and chemotherapy and identify possible modifying factors of radiation-associated risk. This international case-control study pooled data from 4 nested case-control studies of survivors of childhood cancer diagnosed between 1942 and 2000, followed through 2016. Cases were defined as participants diagnosed with a subsequent meningioma. Controls were matched to cases based on sex, age at first cancer diagnosis, and duration of follow-up. Data were analyzed from July 2019 to June 2022. Radiation dose (Gy) to the meningioma site and cumulative chemotherapy doses, including intrathecal and systemic methotrexate doses. The main outcome was subsequent meningioma, assessed using odds ratios (ORs) and excess odds ratios per gray (EOR/Gy). The analysis included 273 survivors of childhood cancer who developed meningioma (cases) and 738 survivors who did not (controls), with a total of 1011 individuals (median [IQR] age at first cancer diagnosis 5.0 [3.0-9.2] years; 599 [59.2%] female). Median (IQR) time since first cancer was 21.5 (15.0-27.0) years. Increasing radiation dose was associated with increased risk of meningioma (EOR/Gy, 1.44; 95% CI, 0.62-3.61), and there was no evidence of departure from linearity (P = .90). Compared with survivors who were not exposed to radiation therapy, those who received doses of 24 Gy or more had more than 30-fold higher odds of meningioma (OR, 33.66; 95% CI, 14.10-80.31). The radiation dose-response association was significantly lower among patients treated at age 10 years or older compared with those treated before age 10 years (EOR/Gy, 0.57; 95% CI, 0.18-1.91 vs 2.20; 95% CI, 0.87-6.31; P for heterogeneity = .03). Risk associated with radiation remained significantly elevated 30 years after exposure (EOR/Gy, 3.76; 95% CI, 0.77-29.15). We found an increased risk of meningioma among children who had received methotrexate (OR, 3.43; 95% CI, 1.56-7.57), but no evidence of a dose-response association or interaction with radiation dose. These findings suggest that the meninges are highly radiosensitive, especially for children treated before age 10 years. These results support the reduction in whole-brain irradiation over recent decades and the prioritization of approaches that limit radiation exposure in healthy tissue for children. The persistence of elevated risks of meningiomas for 30 years after cranial radiotherapy could help inform surveillance guidelines.

Dissecting Stemness in Aggressive Intracranial Meningiomas: Prognostic Role of SOX2 Expression.

Meningiomas are mostly benign tumors that, at times, can behave aggressively, displaying recurrence despite gross-total resection (GTR) and progression to overt malignancy. Such cases represent a clinical challenge, particularly because they are difficult to recognize at first diagnosis. SOX2 (Sex-determining region Y-box2) is a transcription factor with a key role in stem cell maintenance and has been associated with tumorigenesis in a variety of cancers. The purpose of the present work was to dissect the role of SOX2 in predicting the aggressiveness of meningioma. We analyzed progressive/recurrent WHO grade 1–2 meningiomas and WHO grade 3 meningiomas; as controls, non-recurring WHO grade 1 and grade 2 meningioma patients were enrolled. SOX2 expression was evaluated using both immunohistochemistry (IHC) and RT-PCR. The final analysis included 87 patients. IHC was able to reliably assess SOX2 expression, as shown by the good correlation with mRNA levels (Spearman R = 0.0398, p = 0.001, AUC 0.87). SOX2 expression was an intrinsic characteristic of any single tumor and did not change following recurrence or progression. Importantly, SOX2 expression at first surgery was strongly related to meningioma clinical behavior, histological grade and risk of recurrence. Finally, survival data suggest a prognostic role of SOX2 expression in the whole series, both for overall and for recurrence-free survival (p < 0.0001 and p = 0.0001, respectively). Thus, SOX2 assessment could be of great help to clinicians in informing adjuvant treatments during follow-up.

Cancer Risk following Residential Exposure to Airborne Polychlorinated Biphenyls: A Danish Register-Based Cohort Study.

Background:Polychlorinated biphenyls (PCBs) are biopersistent chemicals classified as human carcinogens. This classification is primarily based on evidence on higher-chlorinated PCBs found in food. The carcinogenic potential of airborne lower-chlorinated PCBs remains largely unexplored.Objectives:We aimed to investigate cancer risk following residential exposure to airborne PCBs.Methods:Cancer risk was examined in the Health Effects of PCBs in Indoor Air (HESPAIR) cohort of 38,613 residents of two partly PCB-contaminated residential areas in Greater Copenhagen, identified by nationwide registries. PCB exposure was based on relocation dates and indoor air PCB measurements in subsets of apartments. Cancer diagnoses were extracted from the Danish Cancer Registry for the follow-up period of 1970–2018. We estimated adjusted hazard ratios with time-varying cumulative exposure and a 10-y lag using Cox regression.Results:Overall risk of cancer was not associated with , [hazard ratio (HR) for high-exposed vs. low-exposed ; 95% confidence interval (CI): 0.88, 1.09], but residents exposed to had higher risk of liver cancer (HR ; 95% CI: 1.28, 6.15) and meningiomas (HR ; 95% CI: 1.84, 6.64), with indications of exposure–response relationships. Results were suggestive of a higher risk of pancreatic cancer (HR ; 95% CI: 0.95, 2.64) at the highest aggregated PCB level. For testis cancer, a higher risk was observed among residents exposed to relative to residents exposed to (HR ; 95% CI: 1.41, 6.28), but the risk was not higher for residents exposed to . Apart from this, the risk of specific cancers was similar across exposure groups.Discussion:In this, to our knowledge, first population-based cohort study of residential exposure to airborne PCBs, we found no association between exposure to PCBs in indoor air in private homes and the risk for most of the specific cancers. Higher risk of liver cancer and meningiomas were observed. https://doi.org/10.1289/EHP10605

S2334 Incidentally Diagnosed Triple Cancers Within 2 Years: A Novel Case of Rare Metachronous Cancers, Renal Cell Carcinoma, Cholangiocarcinoma, and Squamous Cell Carcinoma of the Gastroesophageal Junction

Introduction: The gastrointestinal (GI) tract is involved in many familial cancer syndromes usually involving the colon or stomach. We present a patient with 3 rare cancers that were detected within a span of 2 years in a single individual: clear cell renal cell carcinoma (ccRCC), cholangiocarcinoma (CCA), and esophageal squamous cell carcinoma (SCC); a combination not previously described in the literature Case Description/Methods: A 50-year-old male with a history of ccRCC, GERD, and CCA was admitted for evaluation of chronic abdominal pain during chemotherapy for CCA. Regarding his cancer history, ccRCC was incidentally diagnosed 18 months prior on a CT scan for diverticulitis. He underwent a left partial nephrectomy. Surveillance CT imaging 6 months after surgery revealed new incidental liver lesions. Biopsies confirmed metastatic CCA and he started chemotherapy. He noted a 15-year history of episodic abdominal pain and vomiting with no dysphagia or weight loss. Upper endoscopy 16 months prior was normal. He was a former smoker, drank alcohol a few times per month, used marijuana daily, and used cocaine rarely. His family history was significant for multiple cancers at a young age on his maternal side of unknown type. Physical exam showed diffuse abdominal tenderness, worse in the epigastrium without guarding. Labs showed mild anemia, normal BMP/LFTs, and negative H. pylori stool antigen. Upper endoscopy found nodularity adjacent to the esophagogastric junction (EGJ) with abnormal pit pattern under narrow band imaging (Figure). Biopsies confirmed invasive SCC. Staging endoscopic ultrasound showed T3N3 EGJ SCC. He was referred to oncology to discuss treatment options. Genetic testing was positive for BAP1 tumor predisposition syndrome (BAP1-TPDS) Discussion: A review of published literature did not yield a previous description of this combination of cancers in a single individual. BAP1-TPDS is an uncommon autosomal dominant syndrome caused by germline mutation in a tumor suppressor gene. Patients typically present with melanocytic tumors or malignant mesotheliomas but are at risk for RCC, hepatocellular carcinoma, meningioma and CCA. Literature has not revealed esophageal SCC to be associated. In addition to the incidental nature and timing of diagnosis of all 3 of these cancers within a short period of 2 years, the EGJ involvement is unusual. This case suggests atypical EGJ-SCC may be considered as part of the BAP1-TPDS tumor spectrum and warrant additional screening for at-risk individuals.Figure 1.: Left panel showing abnormal nodular mucosa adjacent to the gastro-esophageal junction under high-definition white light imaging. Right panel showing the same area under narrow band imaging.

Risk of intracranial meningioma with three potent progestogens: A population-based case-control study.

Background and purposeA dose‐dependent association between the use of cyproterone acetate (CPA) and intracranial meningioma has been identified but data for other potent progestogens are scarce. The association was assessed between intracranial meningioma surgery and exposure to three potent progestogens: CPA (≥25 mg/day), nomegestrol acetate (NOMAC) (3.75–5 mg/day) and chlormadinone acetate (CMA) (2–10 mg/day).MethodsIn this nationwide population‐based case–control study, cases underwent surgery for intracranial meningioma in France from 2009 to 2018. They were matched to five control subjects for sex, year of birth and area of residence. Progestogen exposure was defined as progestogen use within the year before surgery for cases or the same date for their controls.ResultsIn total, 25,216 cases were included (75% women, median age 58 years). Progestogen exposure was noted for 9.9% of cases (2497/25,216) and 1.9% (2382/126,080) of controls, with an odds ratio (OR) of 6.7 (95% confidence interval [CI] 6.3–7.1). The OR was 1.2 (1.0–1.4) for short‐term use (<1 year) and 9.5 (8.8–10.2) for prolonged use. A strong association was identified for prolonged use of CPA (OR = 22.7, 95% CI 19.5–26.4), NOMAC (OR = 6.5, 95% CI 5.8–7.2) and CMA (OR = 4.7, 95% CI 4.5–5.3). Progestogen exposure increased the risk of meningioma for all histological grades and anatomical sites, particularly for the anterior and middle skull base: OR = 35.7 (95% CI 26.5–48.2) and 23.9 (95% CI 17.8–32.2) for CPA. The estimated number of attributable cases was 2124 (95% CI 2028–2220) (212/year).ConclusionA strong association between prolonged exposure to potent progestogens and surgery for meningioma was observed. The risk increased from CMA to NOMAC to CPA. Individuals should be informed of this risk.

OTHR-31. The molecular profile of secondary meningiomas in survivors of childhood non-central nervous system (CNS) cancers

Abstract INTRODUCTION: Secondary meningiomas are a late effect in children who received cranial irradiation, frequently with a long latency. The molecular genetic profile of primary meningiomas is well studied; however, few studies describe the genomic landscape of radiation-induced meningiomas (RIM). METHODS: Patients followed at the Stollery Children’s Hospital (Edmonton, Canada) with a history of non-CNS malignancies who received cranial irradiation and then developed meningiomas between 1971 and 2013 were identified. Whole exome sequencing (WES), RNA sequencing as well as DNA methylation profiling were performed for patients with available tumor tissue and germline DNA. RESULTS: Of 96 patients who received cranial irradiation for non-CNS tumors, 16 (16.7%) developed symptomatic meningiomas. This patient cohort is unique; all 16 patients identified received 2000-2400 cGy of cranial irradiation, suggesting a threshold dose. 9/16 (56%) had WHO Grade 2 meningiomas or greater and 7/16 (44%) of meningiomas infiltrated other tissues. Post-surgical recurrences occurred in 43%. Patients experienced considerable morbidities directly attributable to the meningiomas or their treatment. 14 patients had samples suitable for further analysis. NF2 mutations were identified in 50% (8; 4 DNA,4 fusion). Other meningioma related genes with mutations identified in other cohorts were not identified. Copy number alternations were noted in all 16 patients in chromosomes 1p and 22q. 850k methylation analysis with PCA as well as UMAP and tSNE did not demonstrate clustering. Ongoing additional studies include examining tumor mutation burden and the radiation mutational profile. CONCLUSIONS: This study examined the RIM in a cohort of patients having received similar doses of radiation for their childhood cancer. There is increased risk of radiation-induced meningioma in survivors of non-CNS cancers given ≥ 2000 cGy during childhood. To date, our findings are consistent with previously described primary and RIM mutations. Enhanced knowledge in secondary meningiomas is crucial for accurate patient counselling, prognostication, and treatment.

Frequency and Relationship between Risk Factors Affecting Recurrence of Cerebral Meningioma in Patients Admitted to Selected Hospitals in Yazd: A 10-Year Study

Introduction: Meningioma is a benign tumor of the brain, which shows a good response to treatment, surgery and benign pathology, but there is a possibility of recurrence. Therefore, the present study was conducted to investigate the relationship between recurrent meningioma risk factors and the rate of meningioma recurrence in Yazd City. Methods: This descriptive-analytical study was performed on all the patients who have surgery for meningioma in Shahid Rahnemoun and Mortaz Hospitals in Yazd City for 10 years. Patient's information, including age, sex, size, grade, diseases and bone changes were extracted from the patients' records. After determining the recurrence status of the disease, information was entered into SPSS version 16 software for Chi-square, Anova and T-test. Results: The most common meningioma was in the age group of 50 to 70 years. In this study, out of 300 patients with meningioma who underwent surgery, 50 (16.7%) had a recurrence of the disease. The recurrence rate was significantly associated with meningioma size, disease grade, and radiotherapy and diabetes (P &lt;0.05). The recurrence rate in this study decreased with the increasing age of the patients. Conclusion: According to the results, considering factors such as age, disease grade, tumor size, radiotherapy and diabetes, which are important predictors of disease recurrence, in managing meningioma patients after surgery and identifying high-risk individuals for disease recurrence are helpful. In the following, due to the involvement of effective factors in the disease, more extensive and retrospective studies are recommended.

A systematic review and meta-analysis of the association between cyproterone acetate and intracranial meningiomas

The influence of exposure to hormonal treatments, particularly cyproterone acetate (CPA), has been posited to contribute to the growth of meningiomas. Given the widespread use of CPA, this systematic review and meta-analysis attempted to assess real-world evidence of the association between CPA and the occurrence of intracranial meningiomas. Systematic searches of Ovid MEDLINE, Embase and Cochrane Controlled Register of Controlled Trials, were performed from database inception to 18th December 2021. Four retrospective observational studies reporting 8,132,348 patients were included in the meta-analysis. There was a total of 165,988 subjects with usage of CPA. The age of patients at meningioma diagnosis was generally above 45 years in all studies. The dosage of CPA taken by the exposed group (n = 165,988) was specified in three of the four included studies. All studies that analyzed high versus low dose CPA found a significant association between high dose CPA usage and increased risk of meningioma. When high and low dose patients were grouped together, there was no statistically significant increase in risk of meningioma associated with use of CPA (RR = 3.78 [95% CI 0.31–46.39], p = 0.190). Usage of CPA is associated with increased risk of meningioma at high doses but not when low doses are also included. Routine screening and meningioma surveillance by brain MRI offered to patients prescribed with CPA is likely a reasonable clinical consideration if given at high doses for long periods of time. Our findings highlight the need for further research on this topic.

Association of allergic diseases and epilepsy with risk of glioma, meningioma and acoustic neuroma: results from the INTERPHONE international case-control study.

We investigated the association of allergic diseases and epilepsy with risk of brain tumours, in Interphone, a 13-country case-control study. Data were obtained from 2693 glioma cases, 2396 meningioma cases, and 1102 acoustic neuroma cases and their 6321 controls. Conditional logistic regression models were used to estimate pooled odds ratios (ORs) and their respective 95% confidence intervals (CIs), adjusted for education and time at interview. Reduced ORs were observed for glioma in relation to physician-diagnosed asthma (OR = 0.73; CI 0.58-0.92), hay fever (OR 0.72; CI 0.61-0.86), and eczema (OR 0.78, CI 0.64-0.94), but not for meningioma or acoustic neuroma. Previous diagnosis of epilepsy was associated with an increased OR for glioma (2.94; CI 1.87-4.63) and for meningioma (2.12; CI 1.27-3.56), but not for acoustic neuroma. This large-scale case-control study adds to the growing evidence that people with allergies have a lower risk of developing glioma, but not meningioma or acoustic neuroma. It also supports clinical observations of epilepsy prior to the diagnosis of glioma and meningioma.

The impact of body mass index and height on risk for primary tumours of the spinal cord, spinal meninges, spinal and peripheral nerves in 1.7 million norwegian women and men: a prospective cohort study

Background Primary tumours of the spinal cord, spinal meninges, spinal and peripheral nerves comprise a heterogenous group of pathology, dominantly represented by meningioma, nerve sheath tumours (NST) and glioma. Body height and body mass index (BMI) are risk factors for certain brain tumour subgroups, but no other study has specifically assessed height and BMI in relation to primary tumours of the spine and peripheral nerves in women and men. Methods In this prospective population-based cohort study height and weight were measured in 1.7 million adult Norwegian women and men at baseline. Incident cases of primary tumours arising from the spinal cord, spinal meninges, spinal and peripheral nerves during follow-up were identified by linkage to the National Cancer Registry. Tumour risk was assessed by Cox regression analyses in relation to height and BMI. Results During 49 million person-years of follow-up, 857 primary tumours of the spinal cord, spinal meninges, spinal and peripheral nerves were identified. Overweight and obesity were not associated with risk for all tumours or any tumour subgroup. Height was positively associated with risk for all tumours (HR per 10 cm increase: 1.30, 95% CI 1.16–1.46). The association between height and tumour risk varied between tumour subgroups: while height was not significantly associated with NST, height increased the risk for meningioma (HR 1.42, 95% CI 1.13–1.78) and glioma (HR 1.56, 95% CI 1.06–2.28). The strongest association between height and tumour risk was found for the glioma subgroup of ependymoma in women (HR 3.38, 95% CI 1.64–6.94). Conclusion This study could not identify overweight and obesity as risk factors for primary tumours of the spinal cord, spinal meninges, spinal and peripheral nerves in women or men. Increasing body height was associated with increased tumour risk overall, but not universal for all tumour subgroups. Importance of the study Primary tumours of the spinal cord, spinal meninges, spinal and peripheral nerves have received little focus in epidemiologic studies, although the incidence and histo-pathological tumour subgroups differ significantly from primary brain tumours. Risk factors for these tumours have hardly been assessed in previous studies. Height, overweight and obesity are known risk factors for several cancers, including certain brain tumour subgroups, such as meningioma. This is the first study to report the association between height, overweight and obesity and primary tumours of the spinal cord, spinal meninges, spinal and peripheral nerves. This includes tumour subgroups of meningioma, nerve sheath tumour, glioma and the most common spinal glioma subgroup of ependymoma. While overweight and obesity were not associated with either of the tumour subgroups, an association between increasing body height and risk for spinal meningioma and glioma, including ependymoma, was found. Nerve sheath tumour risk was not associated with increasing body height.

Birth characteristics and risk of meningioma in a population-based study in California.

We evaluated the potential role of birth characteristics in the etiology of early-onset meningioma. Leveraging a population-based linkage of California birth records (from 1978 to 2015) and cancer registry data (from 1988 to 2015), we identified 362 nonmalignant meningioma cases aged 0-37 years and selected 18 100 controls matched on year of birth. Cases and controls were compared with regard to birth characteristics, with adjusted odds ratios (ORs) and 95% confidence intervals (CIs) estimated from unconditional multivariable logistic regression models. We also conducted stratified analyses by race/ethnicity and age. Female sex (compared to male: OR = 1.43, 95% CI: 1.16 to 1.79; P < .01) and Black race (compared to White: OR = 1.46, 95% CI: 1.02 to 2.07; P = .04) were associated with higher risk of meningioma. Higher birth order (OR = 0.90, 95% CI: 0.81 to 0.99 per additional birth position; P = .04) was associated with a lower risk. No significant associations were observed between birthweight, gestational age, delivery mode, maternal age, or maternal education and meningioma risk. In the non-Latino White subgroup, higher birthweight was associated with a higher risk of meningioma (OR = 1.20, 95% CI: 1.02 to 1.41 per 500 grams; P = .03), but this was not recapitulated in the Latino subgroup. In age-stratified analyses, female sex was a risk factor for those diagnosed at the age of 20-37 years but not among younger individuals. In this large population-based study less prone to selection and recall bias, higher birth order was associated with a reduced risk of early-onset meningioma, while female sex and Black race were linked to an increased risk. There were also indications of differential associations by race/ethnicity and age of diagnosis.

Pleiotropic MLLT10 variation confers risk of meningioma and estrogen-mediated cancers.

BackgroundRisk of tumors of the breast, ovary, and meninges has been associated with hormonal factors and with one another. Genome-wide association studies (GWAS) identified a meningioma risk locus on 10p12 near previous GWAS hits for breast and ovarian cancers, raising the possibility of genetic pleiotropy.MethodsWe performed imputation-based fine-mapping in three case-control datasets of meningioma (927 cases, 790 controls), female breast cancer (28 108 cases, 22 209 controls), and ovarian cancer (25 509 cases, 40 941 controls). Analyses were stratified by sex (meningioma), estrogen receptor (ER) status (breast), and histotype (ovarian), then combined using subset-based meta-analysis in ASSET. Lead variants were assessed for association with additional traits in UK Biobank to identify potential effect-mediators.ResultsTwo-sided subset-based meta-analysis identified rs7084454, an expression quantitative trait locus (eQTL) near the MLLT10 promoter, as lead variant (5.7 × 10–14). The minor allele was associated with increased risk of meningioma in females (odds ratio (OR) = 1.42, 95% Confidence Interval (95%CI):1.20–1.69), but not males (OR = 1.19, 95%CI: 0.91–1.57). It was positively associated with ovarian (OR = 1.09, 95%CI:1.06–1.12) and ER+ breast (OR = 1.05, 95%CI: 1.02–1.08) cancers, and negatively associated with ER– breast cancer (OR = 0.91, 95%CI: 0.86–0.96). It was also associated with several adiposity traits (P < 5.0 × 10–8), but adjusting for body mass index did not attenuate its association with meningioma. MLLT10 and ESR1 expression were positively correlated in normal meninges (P = .058) and meningioma tumors (P = .0065).ConclusionsWe identify a MLLT10 eQTL positively associated with risk of female meningioma, ER+ breast cancer, ovarian cancer, and obesity, and implicate a potential estrogenic mechanism underlying this pleiotropy.

Estrogen and Progesterone Therapy and Meningiomas

Meningiomas are common intracranial tumors with a female predominance. Their etiology is still poorly documented. The role of sexual hormones has long been evoked, and data have been conflicting across studies. However, a dose-dependent relationship between the incidence and growth of meningiomas and hormonal treatment with the progestin cyproterone acetate (CPA) has recently been established. CPA-associated meningiomas seem to be mainly located in the anterior and middle skull base, are more likely to be multiple, may harbor P1K3CA mutations in up to one-third of cases, and are more common with a longer duration of treatment. A similar but lower risk of meningiomas has been recently reported with the use of chlormadinone acetate and nomegestrol acetate as progestin treatments. Concerning hormonal replacement therapy (HRT) in menopausal patients, evidence from epidemiological studies seem to favor an increased risk of meningiomas in treated patients although a recent study failed to show an increased growth of meningiomas in HRT treated vs nontreated patients. Until larger studies are available, it seems wise to recommend avoiding HRT in patients with meningiomas. Evidence from published data does not seem to support an increased risk of meningiomas with oral contraceptive oral contraceptive (OR) use. Data are too scarce to conclude on fertility treatments. Based on studies demonstrating the expression of hormonal receptors in meningiomas, therapies targeting these receptors have been tried but have failed to show an overall favorable clinical outcome in meningioma treatment.

EPID-12. MITOCHONDRIAL DNA SEQUENCE VARIATION AND MENINGIOMA

Abstract Meningiomas are the most common primary central nervous system tumors. Risk factors include female sex, African American race, a higher body mass index, and exposure to ionizing radiation. Genome-wide association studies have identified two risk loci for meningioma in the nuclear genome (rs12770228 and rs2686876). Whereas mitochondrial DNA (mtDNA) sequence variants and haplogroups have been linked with certain cancers, research on meningioma is lacking. We examined the association of 42 common (minor allele frequency ≥ 5%) germline mtDNA variants, haplogroups, and genes with meningioma risk in 1,080 controls and 478 cases from a case-control study conducted at medical centers in the southeastern US. Participant DNA samples were genotyped using the UK Biobank array that included a set of common and rare mtDNA variants. Risk associations were examined separately for meningioma overall, WHO grade 1 (n=409) and WHO grade 2/3 (n=69) meningiomas. Overall, meningioma risk was significantly higher among women (OR=2.86; 95% CI:2.21-3.71) compared to men, higher among African Americans (OR=2.37, 95% CI:1.41-3.99) compared to Caucasians, and higher among those who were overweight (OR=1.48; 95% CI:1.11-1.98) or obese (OR= 1.73; 95% CI:1.26-2.38) compared to those of normal weight. The variant m.16362T &amp;gt;C (rs62581341) in the mitochondrial control region was positively associated with grade 2/3 meningiomas (OR=2.33; 95% CI: 1.14-4.79), but not with grade 1 tumors (OR=0.99; 95% CI:0.64-1.53). Haplogroup L, a marker for African ancestry, was identified among 3.6% of controls and 8.6% of cases and was associated with meningioma risk overall (OR=2.56; 95% CI:1.52-4.30). When stratifying by self-reported race, the association between haplogroup L and meningioma was only apparent among the small number of self-reported Caucasians with this haplogroup (OR=6.68; 95% CI=1.66-26.91) when compared to non-L haplogroups, combined. No other common mtDNA variant (minor allele &amp;gt;5%), haplogroup, or gene was associated with meningioma risk. These findings merit further study.

BIOM-40. TARGETED GENE EXPRESSION PROFILING PREDICTS MENINGIOMA OUTCOMES AND RADIOTHERAPY RESPONSES

Abstract BACKGROUND Surgery is the mainstay of meningioma treatment, but improvements in meningioma risk stratification are needed and indications for postoperative radiotherapy are controversial. DNA methylation profiling, copy number variants (CNVs), exome sequencing, and RNA sequencing have improved understanding of meningioma biology, but have not superseded histologic grading, or revealed biomarkers for radiotherapy responses. To address these unmet needs, we optimized and validated a targeted gene expression biomarker predicting meningioma outcomes and responses to radiotherapy. METHODS Targeted gene expression profiling was performed on a discovery cohort of 173 meningiomas (median follow-up 8.1 years) and a validation cohort of 331 meningiomas (median follow-up 6.1 years) treated with surgery (n=504) and postoperative radiotherapy (n=73) at independent, international institutions (70% WHO grade 1, 24% WHO grade 2, 6% WHO grade 3). Optimized targeted gene expression models predicting clinical outcomes (34 genes) or radiotherapy responses (12 genes) were developed from the discovery cohort, and compared to histologic and molecular classification systems by performing DNA methylation profiling, CNV analysis, exome sequencing, and RNA sequencing on the same meningiomas. RESULTS Targeted gene expression profiling achieved a concordance-index of 0.75 ± 0.03 (SEM) for local freedom from recurrence (LFFR) and 0.72 ± 0.03 for overall survival (OS) in the validation cohort, outperforming WHO grade (5-year LFFR delta-AUC 0.15, 95% CI 0.076-0.229, p=0.001) and DNA methylation grouping (delta-AUC 0.075, 95% CI 0.006-0.130, p=0.01) for LFFR, disease-specific survival, and OS. The biomarker was independently prognostic after accounting for WHO grade, extent of resection, primary versus recurrent presentation, CNV status, DNA methylation group, and Ki67 labeling index, and identified meningiomas benefiting from radiotherapy (interaction p-value=0.0008), suggesting postoperative radiotherapy could be refined in 30.2% of cases. CONCLUSIONS Targeted gene expression profiling of 504 meningiomas improves discrimination of meningioma local recurrence, disease-specific survival, and overall survival, and predicts radiotherapy responses.

A decreased risk of meningioma in women smokers was only observed in American studies rather than studies conducted in other countries: a systematic review and meta-analysis

BackgroundWhether smoking is related to a decreased risk of meningioma in women is still controversial. We conducted a systematic review and meta-analysis examining the association between smoking and risk of meningiomas in women.MethodsTwo authors independently performed a systematic literature review in the PubMed, Cochrane Library, and EMBASE databases. We identified case-control and cohort studies quantifying associations between smoking and risk of meningioma in women. A meta-analysis by pooling studies was performed according to the multivariate-adjusted risk estimates and 95% confidence intervals (CIs) preferentially. We further conducted additional subgroup and sensitivity analyses to explore possible explanations of the results.ResultsA total of seven observational studies were included, with a total of 2132 female patients diagnosed with meningiomas. Ever smoking was associated with a significantly reduced risk of meningioma in women, with pooled odds ratio (OR) of 0.83 (95% CI 0.70–0.98). Similar findings were noted for current (OR 0.78, 95% CI 0.66–0.93) and past (OR 0.82, 95% CI 0.71–0.94) smokers. However, considering the areas, the OR of ever smoking was 0.77 (95% CI 0.68–0.87) in three American studies, but 0.99 (95% CI 0.73–1.35) in four studies conducted in other countries.ConclusionsBased on limited epidemiological evidence, a decreased risk of meningioma in women smokers was only observed in American studies rather than studies conducted in other countries.

Mitochondrial DNA sequence variation and risk of meningioma.

Risk factors for meningioma include female gender, African American race, high body mass index (BMI), and exposure to ionizing radiation. Although genome-wide association studies (GWAS) have identified two nuclear genome risk loci for meningioma (rs12770228 and rs2686876), the relation between mitochondrial DNA (mtDNA) sequence variants and meningioma is unknown. We examined the association of 42 common germline mtDNA variants (minor allele frequency ≥ 5%), haplogroups, and genes with meningioma in 1080 controls and 478 meningioma cases from a case-control study conducted at medical centers in the southeastern United States. Associations were examined separately for meningioma overall and by WHO grade (n = 409 grade I and n = 69 grade II/III). Overall, meningioma was significantly associated with being female (OR 2.85; 95% CI 2.21-3.69), self-reported African American race (OR 2.38, 95% CI 1.41-3.99), and being overweight (OR 1.48; 95% CI 1.11-1.97) or obese (OR 1.70; 95% CI 1.25-2.31). The variant m.16362T > C (rs62581341) in the mitochondrial control region was positively associated with grade II/III meningiomas (OR 2.33; 95% CI 1.14-4.77), but not grade I tumors (OR 0.99; 95% CI 0.64-1.53). Haplogroup L, a marker for African ancestry, was associated with meningioma overall (OR 2.92; 95% CI 1.01-8.44). However, after stratifying by self-reported race, this association was only apparent among the few self-reported Caucasians with this haplogroup (OR 6.35; 95% CI 1.56-25.9). No other mtDNA variant, haplogroup, or gene was associated with meningioma. Common mtDNA variants and major mtDNA haplogroups do not appear to have associations with the odds of developing meningioma.

Diagnostic radiological examinations and risk of intracranial tumours in adults-findings from the Interphone Study.

BackgroundExposure to high doses of ionizing radiation is among the few well-established brain tumour risk factors. We used data from the Interphone study to evaluate the effects of exposure to low-dose radiation from diagnostic radiological examinations on glioma, meningioma and acoustic neuroma risk.MethodsBrain tumour cases (2644 gliomas, 2236 meningiomas, 1083 neuromas) diagnosed in 2000–02 were identified through hospitals in 13 countries, and 6068 controls (population-based controls in most centres) were included in the analysis. Participation across all centres was 64% for glioma cases, 78% for meningioma cases, 82% for acoustic neuroma cases and 53% for controls. Information on previous diagnostic radiological examinations was obtained by interviews, including the frequency, timing and indication for the examinations. Typical brain doses per type of examination were estimated based on the literature. Examinations within the 5 years before the index date were excluded from the dose estimation. Adjusted odds ratios were estimated using conditional logistic regression.ResultsNo materially or consistently increased odds ratios for glioma, meningioma or acoustic neuroma were found for any specific type of examination, including computed tomography of the head and cerebral angiography. The only indication of an elevated risk was an increasing trend in risk of meningioma with the number of isotope scans, but no such trends for other examinations were observed. No gradient was found in risk with estimated brain dose. Age at exposure did not substantially modify the findings. Sensitivity analyses gave results consistent with the main analysis.ConclusionsThere was no consistent evidence for increased risks of brain tumours with X-ray examinations, although error from selection and recall bias cannot be completely excluded. A cautious interpretation is warranted for the observed association between isotope scans and meningioma.