Genomic and biochemical mechanisms and external drivers underlying differences in meningioma clinical outcomes

PROJECT 1: PROJECT SUMMARY The World Health Organization (WHO) has historically graded meningiomas according to histological features, and many WHO grade 1 meningiomas can be effectively treated with surgery or radiotherapy. Many WHO grade 2 or grade 3 meningiomas, which are malignant, are resistant to treatment and cause significant neurological morbidity and mortality. Meningiomas are the only brain tumors that are more common in Black individuals than in White individuals, and Black individuals have higher rates of meningioma recurrence despite having similar extents of resection as non-Black individuals. These data indicate that there are urgent, unmet needs for new treatments and predictive biomarkers to improve and individualize meningioma treatments, but the biological mechanisms, external and environmental drivers and individual-level risk factors that may underlie differences in meningioma incidence or outcomes are incompletely understood. Using data from the Central Brain Tumor Registry of the United States (CBTRUS), we showed that Black individuals have 57% higher risk of developing malignant meningiomas than White individuals. Using multiplatform molecular profiling on 2092 meningiomas from 13 institutions across predominantly White populations, we developed DNA methylation and gene expression biomarkers that suggest meningiomas from Black individuals are enriched in high-risk molecular features that underlie therapeutic vulnerabilities. These preliminary data provide an epidemiological and molecular framework for defining and addressing differences in meningioma incidence and outcomes among various populations. Our central hypothesis is that tumor biology, external drivers, and individual-level risk factors underlie differences in clinical outcomes. Our objective is to understand mechanisms driving meningioma to establish the generalizability of predictive DNA methylation and gene expression biomarkers and provide data to support new treatments for specific populations of patients with meningiomas. To do so, we will integrate retrospective and prospective human samples, bioinformatics, preclinical models, and epidemiological data from 5 institutions. We will to define the molecular architecture of meningiomas from Black individuals compared to White individuals and evaluate the impact of external drivers and individual-level risk factors (Aim 1), define how an enigmatic progesterone receptor (PGRMC1) drives meningioma growth (Aim 2), and develop therapeutics to block PGRMC1 in meningiomas (Aim 3). Successful completion of this project will define tumor biology, external drivers, and individual-level risk factors that underlie differences in meningioma clinical outcomes across various populations and provide data to support predictive biomarkers and new treatments.