Kyle Walsh

Gliomas are the most prevalent neurological cancer in the USA and care modalities are not able to effectively combat these aggressive malignancies. Identifying new, more effective treatments require a deep understanding of the complex genetic variations and relevant pathway associations behind these cancers. Drawing connections between gene mutations with a responsive genetic target can help drive therapy selections to enhance patient survival. We have performed extensive molecular profiling of the Capicua gene (CIC), a tumor and transcriptional suppressor gene, and its mutation prevalence in reference to MAPK activation within clinical glioma tissue. CIC mutations occur far more frequently in oligodendroglioma (52.1%) than in low-grade astrocytoma or glioblastoma. CIC-associated mutations were observed across all glioma subtypes, and MAPK-associated mutations were most prevalent in CIC wild-type tissue regardless of the glioma subtype. MAPK activation, however, was enhanced in CIC-mutated oligodendroglioma. The totality of our observations reported supports the use of CIC as a relevant genetic marker for MAPK activation. Identification of CIC mutations, or lack thereof, can assist in selecting, implementing, and developing MEK/MAPK-inhibitory trials to improve patient outcomes potentially.

BACKGROUND: Previous research has identified older age, African-American race, and female sex as meningioma risk factors, but there is limited information on their joint effects, or on how these demographic factors vary across strata of tumor grade. METHODS: The Central Brain Tumor Registry of the United States (CBTRUS) is a population-based registry combining data from the CDC's National Program of Cancer Registries and NCI's Surveillance, Epidemiology and End Results Program which covers ~100% of the U.S. population and aggregates incidence data on all primary malignant and nonmalignant brain tumors. These data were used to explore the joint impacts of sex and race/ethnicity on average annual age-adjusted incidence rates of meningioma. We calculated meningioma incidence rate ratios (IRRs) by sex and race/ethnicity, across strata of age and tumor grade. RESULTS: Compared to individuals who are non-Hispanic White, individuals who are non-Hispanic Black had significantly higher risk of grade 1 (IRR = 1.23; 95% CI: 1.21-1.24) and grade 2-3 meningioma (IRR = 1.42; 95% CI: 1.37-1.47). The female-to-male IRR peaked in the fifth decade of life across all racial/ethnic groups and tumor grades, but was 3.59 (95% CI: 3.51-3.67) for WHO grade 1 meningioma and 1.74 (95% CI: 1.63-1.87) for WHO grade 2-3 meningioma. CONCLUSIONS: This study reveals the joint effects of sex and race/ethnicity on meningioma incidence throughout the lifespan and across strata of tumor grade, highlighting incidence disparities among females and African-Americans that may inform future strategies for tumor interception.

BACKGROUND: Risk 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. METHODS: We 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. RESULTS: Two-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). CONCLUSIONS: We 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.