Zhou Wenjia, Zhang Junhua
CEMS, NCMIS, RCSDS, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing, China.
School of Mathematical Sciences, University of Chinese Academy of Sciences, Beijing, China.
PLoS Comput Biol. 2025 Aug 6;21(8):e1013349. doi: 10.1371/journal.pcbi.1013349. eCollection 2025 Aug.
Discovery of cancer driver pathways is essential for targeted therapies, since these pathways govern tumor progression and treatment resistance. However, their context-specific patterns across populations remain poorly understood. Leveraging pan-cancer genomic data, we apply our two models, EntCDP and ModSDP, to perform stratified analyses from four perspectives: region, tumor type, age group, and risk factors. Our results reveal the regional biases in perturbed pathways, such as PI3K-Akt in Chinese patients and GPCR in American patients with bladder cancer. Subtype comparisons highlight the mTOR signaling in lung adenocarcinoma and the FoxO signaling in lung squamous cell carcinoma. Pediatric-adult comparisons emphasize the enrichment of Ras signaling in pediatric acute myeloid leukemia and PAK signaling in pediatric glioblastoma, respectively. Risk factor associations further link Notch-mediated pathways to alcohol consumption and CDKN-regulated pathways to obesity-related cancers. Our findings demonstrate the utility of stratified driver pathway analysis in uncovering common and specific mechanisms, which can help prioritize context-aware therapeutic targets.
发现癌症驱动通路对于靶向治疗至关重要，因为这些通路控制着肿瘤进展和治疗抗性。然而，它们在不同人群中的特定背景模式仍知之甚少。利用泛癌基因组数据，我们应用我们的两种模型EntCDP和ModSDP，从四个角度进行分层分析：地区、肿瘤类型、年龄组和风险因素。我们的结果揭示了受干扰通路中的区域偏差，例如中国膀胱癌患者中的PI3K-Akt通路和美国膀胱癌患者中的GPCR通路。亚型比较突出了肺腺癌中的mTOR信号传导和肺鳞状细胞癌中的FoxO信号传导。儿童与成人的比较分别强调了Ras信号传导在儿童急性髓细胞白血病中的富集以及PAK信号传导在儿童胶质母细胞瘤中的富集。风险因素关联进一步将Notch介导的通路与饮酒联系起来，并将CDKN调节的通路与肥胖相关癌症联系起来。我们的研究结果证明了分层驱动通路分析在揭示共同和特定机制方面的实用性，这有助于确定上下文感知治疗靶点的优先级。
