Sex Differences In The Genomic Profiles Of Medulloblastoma Subtypes.

Abstract Medulloblastoma (MB), the most common malignant brain tumor in children, has marked sex differences within molecular subtypes such that males are more frequently diagnosed with SHH, Group 3 and 4 tumors, which have worse prognoses than WNT tumors. Using publicly available data by Cavalli et al. (Cancer Cell, 2017), we identified sex differences in MB methylation and gene expression to uncover sexually dimorphic genomic profiles and biologic pathways to better understand the role of sex in MB subtype biology. There were statistically significant differences in sex by MB subtype (p-value=0.0005): Group 3 (n=144; 65% male), Group 4 (n=326; 67% male), SHH (n=223; 57% male) and WNT (n=70; 41% male). Females had statistically significantly worse survival than males for SHH (Log-Rank p-value=0.02; female 5-year survival 71%, male 85%; Hazard Ratio: 2.39; 95% Confidence Interval: 1.16-4.77). There were no sex differences in survival for other subtypes. In differential gene expression analyses using microarray data, few genes had statistically significant sexually dimorphic expression patterns (Group 3: 25 genes; Group 4: 65 genes; SHH: 37 genes; WNT: 32 genes). Ingenuity Pathway Analysis on the top 200 genes for each subtype found no sexually dimorphic pathways shared between all subtypes. Sex differences in Regulation of eIF4 and p70S6K Signaling, which has an important role in the mTOR pathway, was shared in WNT, SHH and Group 4 tumors. There were sex differences in VEGF and androgen signaling in WNT, EMT and IL-23 signaling in SHH, NF-KB and IL-8 signaling in Group 3, and mTOR and AMPK signaling in Group 4. Due to immune system sex differences, we examined MB immune cell composition, which may underlie sex differences in MB severity. We applied the LM22 signature and identified differences in most immune cell types between MB subtypes including M2 macrophages, CD8 T cells, and activated NK cells (all p<0.001). By sex, Group 3 females had higher plasma cell levels (p-value <0.01), WNT females had higher memory resting CD4 T cells (p<0.05), and WNT males had higher levels of activated NK cells (p<0.05). Concerning methylation on the autosomes, differentially methylated regions (DMR) by sex were identified in each subtype, with the largest number in SHH (n=398). Forty-four sex-specific DMR were shared across subtypes. Unsupervised hierarchical clustering showed nearly complete differentiation of samples by sex for each subtype when using DMR that differed significantly by sex. Females had more DMR with higher methylation than males in all subtypes. In pathway analysis among genes with higher methylation in females (Q-value<0.05), signaling pathways for IGF-1, HIF1α, TGF-β, ERK/MAPK and the Th1 pathway were identified. Collectively, these findings highlight sexually dimorphic genomic profiles for children with MB, particularly in SHH where survival differences were observed, which may help identify sex-specific therapeutic targets in the future. Citation Format: Rachel M. Moss, Natali Sorajja, Lauren J. Mills, Christopher L. Moertel, Logan G. Spector, David A. Largaespada, Lindsay A. Williams. Sex differences in the genomic profiles of medulloblastoma subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3026.