Oligodendroglioma, IDH-mutant and 1p/19q-codeleted has highly variable outcomes that are strongly influenced by patient age. The distribution of oligodendroglioma age is non-Gaussian and reportedly bimodal, which motivated our investigation of age-associated molecular alterations that may drive poorer outcomes. We found that elevated HOXD12 expression was associated with both older patient age and shorter survival in the TCGA (FDR < 0.01, FDR = 1e−5) and the CGGA (p = 0.03, p < 1e−3). HOXD12 gene body hypermethylation was associated with older age, higher WHO grade, and shorter survival in the TCGA (p < 1e−6, p < 0.001, p < 1e−3) and with older age and higher WHO grade in Capper et al. (p < 0.002, p = 0.014). In the TCGA, HOXD12 gene body hypermethylation and elevated expression were independently prognostic of NOTCH1 and PIK3CA mutations, loss of 15q, MYC activation, and standard histopathological features. Single-nucleus RNA and ATAC sequencing data showed that HOXD12 activity was elevated in neoplastic tissue, particularly within cycling and OPC-like cells, and was associated with a stem-like phenotype. A pan-HOX DNA methylation analysis revealed an age and survival-associated HOX-high signature that was tightly associated with HOXD12 gene body methylation. Overall, HOXD12 expression and gene body hypermethylation were associated with an older, atypically aggressive subtype of oligodendroglioma.

少突胶质细胞瘤、IDH 突变和 1p/19q 基因缺失的结果差异很大，且受患者年龄的影响很大。少突胶质细胞瘤的年龄分布是非高斯分布，据报道是双峰的，这促使我们研究与年龄相关的分子改变，这些改变可能会导致较差的结果。我们发现，在 TCGA (FDR < 0.01，FDR = 1e−5) 和 CGGA ( p = 0.03， p < 1e−3) 中，HOXD12 表达升高与患者年龄较大和生存期较短相关。 HOXD12基因体高甲基化与 TCGA 中年龄较大、WHO 等级较高和生存期较短相关（ p < 1e−6、 p < 0.001、 p < 1e−3），而 Capper 中 HOXD12 基因体高甲基化与年龄较大和 WHO 等级较高相关等人。 （ p < 0.002， p = 0.014）。在 TCGA 中， HOXD12基因体高甲基化和表达升高是NOTCH1和PIK3CA突变、15q 缺失、MYC 激活和标准组织病理学特征的独立预后。单核 RNA 和 ATAC 测序数据表明，HOXD12 活性在肿瘤组织中升高，特别是在循环细胞和 OPC 样细胞中，并且与干细胞样表型相关。泛 HOX DNA 甲基化分析揭示了与年龄和生存相关的 HOX-high 特征，该特征与HOXD12基因体甲基化密切相关。总体而言，HOXD12 表达和基因体高甲基化与一种较古老的、非典型侵袭性的少突胶质细胞瘤亚型相关。