Moss Rachel M, Sorajja Natali, Mills Lauren J, Moertel Christopher L, Hoang Thanh T, Spector Logan G, Largaespada David A, Williams Lindsay A
Division of Epidemiology & Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, MN, United States.
Bioinformatics and Computational Biology, University of Minnesota, Minneapolis, MN, United States.
Front Oncol. 2023 Mar 24;13:1113121. doi: 10.3389/fonc.2023.1113121. eCollection 2023.
Medulloblastoma, the most common malignant pediatric brain tumor, displays marked sex differences in prevalence of the four main molecular subgroups: SHH, WNT, Group 3 and Group 4. Males are more frequently diagnosed with SHH, Group 3 and 4 tumors, which have worse prognoses than WNT tumors. Little is known about sex differences in methylation profiles within subgroups.
Using publicly available methylation data (Illumina HumanMethylation450K array), we compared beta values for males versus females. Differentially methylated positions (DMP) by sex within medulloblastoma subgroups were identified on the autosomes. DMPs were mapped to genes and Reactome pathway analysis was run by subgroup. Kaplan-Meier survival curves (Log-Rank p-values) were assessed for each sex within subgroup. was used to investigate the tumor microenvironment using deconvolution to estimate the abundances of immune cell types using DNA methylation data.
There were statistically significant differences in sex by medulloblastoma subgroups (chi-squared p-value=0.00004): 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 worse survival than males for SHH (p-value=0.02). DMPs by sex were identified within subgroups: SHH (n=131), Group 4 (n=29), Group 3 (n=19), and WNT (n=16) and validated in an independent dataset. Unsupervised hierarchical clustering showed that sex-DMPs in SHH did not correlate with other tumor attributes. Ten genes with sex DMPs (, , , , , , , , , and were shared across subgroups. Significant pathways (p<0.05) associated with DMPs were identified for SHH (n=22) and Group 4 (n=4) and included signaling pathways for RET proto-oncogene, advanced glycosylation end product receptor, regulation of KIT, neurotrophic receptors, NOTCH, and TGF-β. In SHH, we identified DMPs in four genes (, , , that encode proteins which are the target of therapies in clinical trials for other cancers. There were few sex differences in immune cell composition within tumor subgroups.
There are sexually dimorphic methylation profiles for SHH medulloblastoma where survival differences were observed. Sex-specific therapies in medulloblastoma may impact outcomes.
髓母细胞瘤是最常见的儿童恶性脑肿瘤，在四种主要分子亚组（SHH、WNT、3组和4组）的患病率上存在显著的性别差异。男性更常被诊断为SHH、3组和4组肿瘤，这些肿瘤的预后比WNT肿瘤更差。关于亚组内甲基化谱的性别差异知之甚少。
利用公开的甲基化数据（Illumina HumanMethylation450K芯片），我们比较了男性和女性的β值。在常染色体上确定了髓母细胞瘤亚组内按性别区分的差异甲基化位点（DMP）。将DMP映射到基因上，并按亚组进行Reactome通路分析。评估每个亚组内每种性别的Kaplan-Meier生存曲线（对数秩p值）。利用反卷积方法，通过DNA甲基化数据估计免疫细胞类型的丰度，以研究肿瘤微环境。
髓母细胞瘤亚组之间在性别上存在统计学显著差异（卡方p值=0.00004）：3组（n=144；65%为男性）、4组（n=326；67%为男性）、SHH（n=223；57%为男性）和WNT（n=70；41%为男性）。在SHH亚组中，女性的生存率低于男性（p值=0.02）。在亚组内确定了按性别区分的DMP：SHH（n=131）、4组（n=29）、3组（n=19）和WNT（n=16），并在独立数据集中得到验证。无监督层次聚类显示，SHH中的性别DMP与其他肿瘤特征不相关。10个具有性别DMP的基因（、、、、、、、、和）在各亚组中均有共享。确定了与DMP相关的显著通路（p<0.0
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