APOE expression is associated with molecular class, context‐dependent survival and myeloid immune features in lower‐grade glioma
Jiajun Xu, Lin Yang, Yanlong Ma, Yanhui Peng, Juncheng Wang, Wenping LiuAbstract
Background
The APOE gene encodes ApoE, a lipid‐transport protein implicated in neuroinflammatory processes. Whether APOE expression independently predicts outcome in lower‐grade glioma (LGG), after accounting for IDH mutation and 1p/19q codeletion, remains unclear.
Methods
We analysed The Cancer Genome Atlas (TCGA) pan‐cancer and LGG transcriptomic and clinical data. In LGG, APOE was modelled continuously in Cox regression adjusted for age, histological grade and IDH/1p/19q molecular class; molecular‐class‐stratified and interaction analyses were performed. Results were evaluated in the Chinese Glioma Genome Atlas (CGGA)_693 and CGGA_325 cohorts. Immune deconvolution, myeloid/lipid programme scores and author‐annotated GSE197543 single‐cell data were used to define the immune and cellular context of APOE .
Results
Higher APOE expression was associated with favourable survival in univariable TCGA‐LGG analyses, but not after adjustment for molecular class (overall survival hazard ratio per 1‐SD increase, 1.021; 95% confidence interval, 0.830–1.256; p = 0.846). The APOE –survival association differed across molecular classes (global interaction p = 1.92 × 10 −4 ), including an adverse association in IDH‐wild‐type tumours. External results were heterogeneous: the unadjusted association in CGGA_693 attenuated after adjustment and was not consistently reproduced in CGGA_325. APOE correlated positively with tumour‐associated macrophage/macrophage transcriptional programmes in TCGA and both CGGA cohorts. Single‐cell data localised APOE expression primarily to microglial and macrophage populations.
Conclusion
The apparent favourable association between APOE and LGG survival is molecular‐context dependent and not consistently independent across cohorts. APOE may primarily mark a myeloid immune–metabolic context rather than an independently protective prognostic determinant.