Department of Neurology, School of Medicine, University of California, Davis, Sacramento, CA, USA.
Clinical and Translational Neuroscience Unit, Department of Neurology, Weill Cornell Medicine, Feil Family Brain and Mind Research Institute, New York, NY, USA.
Ann Neurol. 2024 Sep;96(3):565-581. doi: 10.1002/ana.26997. Epub 2024 Jun 14.
Approximately half of ischemic strokes (IS) in cancer patients are cryptogenic, with many presumed cardioembolic. We evaluated whether there were specific miRNA and mRNA transcriptome architectures in peripheral blood of IS patients with and without comorbid cancer, and between cardioembolic versus noncardioembolic IS etiologies in comorbid cancer.
We studied patients with cancer and IS (CS; n = 42), stroke only (SO; n = 41), and cancer only (n = 28), and vascular risk factor-matched controls (n = 30). mRNA-Seq and miRNA-Seq data, analyzed with linear regression models, identified differentially expressed genes in CS versus SO and in cardioembolic versus noncardioembolic CS, and miRNA-mRNA regulatory pairs. Network-level analyses identified stroke etiology-specific responses in CS.
A total of 2,085 mRNAs and 31 miRNAs were differentially expressed between CS and SO. In CS, 122 and 35 miRNA-mRNA regulatory pairs, and 5 and 3 coexpressed gene modules, were associated with cardioembolic and noncardioembolic CS, respectively. Complement, growth factor, and immune/inflammatory pathways showed differences between IS etiologies in CS. A 15-gene biomarker panel assembled from a derivation cohort (n = 50) correctly classified 81% of CS and 71% of SO participants in a validation cohort (n = 33). Another 15-gene panel correctly identified etiologies for 13 of 13 CS-cardioembolic and 11 of 11 CS-noncardioembolic participants upon cross-validation; 11 of 16 CS-cryptogenic participants were predicted cardioembolic.
We discovered unique mRNA and miRNA transcriptome architecture in CS and SO, and in CS with different IS etiologies. Cardioembolic and noncardioembolic etiologies in CS showed unique coexpression networks and potential master regulators. These may help distinguish CS from SO and identify IS etiology in cryptogenic CS patients. ANN NEUROL 2024;96:565-581.
约一半癌症患者的缺血性脑卒中（IS）为隐源性，其中许多被认为是心源性栓塞。我们评估了是否存在外周血中特定的微小 RNA（miRNA）和 mRNA 转录组结构，这些结构存在于患有合并癌症的 IS 患者和无合并癌症的 IS 患者之间，以及存在合并癌症的心源性栓塞性 IS 与非心源性栓塞性 IS 病因之间。
我们研究了患有癌症和 IS（CS；n=42）、单纯性脑卒中（SO；n=41）以及单纯性癌症（n=28）的患者，以及血管危险因素匹配的对照组（n=30）。使用线性回归模型分析 mRNA-Seq 和 miRNA-Seq 数据，以鉴定 CS 与 SO 之间以及 CS 中心源性栓塞与非心源性栓塞之间差异表达的基因，以及 miRNA-mRNA 调控对。网络级分析确定了 CS 特定的中风病因反应。
CS 与 SO 之间共有 2085 个 mRNAs 和 31 个 miRNA 差异表达。在 CS 中，122 个和 35 个 miRNA-mRNA 调控对，以及 5 个和 3 个共表达基因模块，分别与心源性栓塞和非心源性栓塞 CS 相关。补体、生长因子和免疫/炎症途径在 CS 的 IS 病因之间存在差异。从一个验证队列（n=33）中由 50 名患者组成的推导队列组装的 15 个基因生物标志物面板正确分类了 81%的 CS 和 71%的 SO 参与者。另一个 15 个基因面板在交叉验证中正确识别了 13 名 CS-心源性栓塞和 11 名 CS-非心源性栓塞患者的病因；16 名 CS-隐源性患者中的 11 名被预测为心源性栓塞。
我们在 CS 和 SO 以及 CS 中不同的 IS 病因中发现了独特的 mRNA 和 miRNA 转录组结构。CS 中心源性栓塞和非心源性栓塞的病因表现出独特的共表达网络和潜在的主调控因子。这些可能有助于将 CS 与 SO 区分开来，并确定隐源性 CS 患者的 IS 病因。
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