HOXD12 defines an age-related aggressive subtype of oligodendroglioma

IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY
Nicholas Nuechterlein, Sadie Cimino, Allison Shelbourn, Vinny Ha, Sonali Arora, Sharika Rajan, Linda G. Shapiro, Eric C. Holland, Kenneth Aldape, Tresa McGranahan, Mark R. Gilbert, Patrick J. Cimino
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Abstract

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.

Abstract Image

HOXD12定义了一种与年龄相关的侵袭性少突胶质细胞瘤亚型
IDH突变和1p/19q编码缺失的少突胶质细胞瘤的预后变化很大,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,据报道是双峰分布,这促使我们研究可能导致较差预后的年龄相关分子改变。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增大和生存期缩短有关。在TCGA(p <1e-6,p <0.001,p <1e-3)和Capper等(p <0.002,p = 0.014)中,HOXD12基因体超甲基化与年龄较大、WHO分级较高和生存期较短有关。在TCGA中,HOXD12基因体超甲基化和表达升高与NOTCH1和PIK3CA突变、15q缺失、MYC活化和标准组织病理学特征无关。单核 RNA 和 ATAC 测序数据显示,HOXD12 活性在肿瘤组织中升高,尤其是在循环细胞和 OPC 样细胞中,并且与干样表型相关。泛HOX DNA甲基化分析显示,与年龄和存活率相关的HOX-高特征与HOXD12基因体甲基化密切相关。总体而言,HOXD12的表达和基因体的高甲基化与年龄较大、侵袭性不典型的少突胶质细胞瘤亚型有关。
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来源期刊
Acta Neuropathologica
Acta Neuropathologica 医学-病理学
CiteScore
23.70
自引率
3.90%
发文量
118
审稿时长
4-8 weeks
期刊介绍: Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.
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