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

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.