整合药物基因组学揭示了肺腺癌中具有不同免疫格局和特定治疗反应的三种亚型。
Integrative pharmacogenomics revealed three subtypes with different immune landscapes and specific therapeutic responses in lung adenocarcinoma.
作者信息
Ge Xiaoyong, Liu Zaoqu, Weng Siyuan, Xu Hui, Zhang Yuyuan, Liu Long, Dang Qin, Guo Chunguang, Beatson Richard, Deng Jinhai, Han Xinwei
机构信息
Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
Interventional Institute of Zhengzhou University, Zhengzhou, Henan 450052, China.
出版信息
Comput Struct Biotechnol J. 2022 Jul 2;20:3449-3460. doi: 10.1016/j.csbj.2022.06.064. eCollection 2022.
BACKGROUND
Pharmacogenomics is crucial for individualized drug therapy and plays an increasingly vital role in precision medicine decision-making. However, pharmacogenomics-based molecular subtypes and their potential clinical significance remain primarily unexplored in lung adenocarcinoma (LUAD).
METHODS
A total of 2065 samples were recruited from eight independent cohorts. Pharmacogenomics data were generated from the profiling of relative inhibition simultaneously in mixtures (PRISM) and the genomics of drug sensitivity in cancer (GDSC) databases. Multiple bioinformatics approaches were performed to identify pharmacogenomics-based subtypes and find subtype-specific properties.
RESULTS
Three reproducible molecular subtypes were found, which were independent prognostic factors and highly associated with stage, survival status, and accepted molecular subtypes. Pharmacogenomics-based subtypes had distinct molecular characteristics: S-Ⅰ was inflammatory, proliferative, and immune-evasion; S-Ⅱ was proliferative and genetics-driven; S-III was metabolic and methylation-driven. Finally, our study provided subtype-guided personalized treatment strategies: Immune checkpoint blockers (ICBs), doxorubicin, tipifarnib, AZ628, and AZD6244 were for S-Ⅰ; Cisplatin, camptothecin, roscovitine, and A.443654 were for S-Ⅱ; Docetaxel, paclitaxel, vinorelbine, and BIBW2992 were for S-III.
CONCLUSION
We provided a novel molecular classification strategy and revealed three pharmacogenomics-based subtypes for LUAD patients, which uncovered potential subtype-related and patient-specific therapeutic strategies.
背景
药物基因组学对于个体化药物治疗至关重要，在精准医学决策中发挥着越来越重要的作用。然而，基于药物基因组学的分子亚型及其潜在的临床意义在肺腺癌（LUAD）中仍主要未被探索。
方法
从八个独立队列中招募了总共2065个样本。药物基因组学数据来自混合物中相对抑制的分析（PRISM）和癌症药物敏感性基因组学（GDSC）数据库。采用多种生物信息学方法来识别基于药物基因组学的亚型并发现亚型特异性特征。
结果
发现了三种可重复的分子亚型，它们是独立的预后因素，并且与分期、生存状态和公认的分子亚型高度相关。基于药物基因组学的亚型具有不同的分子特征：S-Ⅰ型具有炎症、增殖和免疫逃逸特性；S-Ⅱ型具有增殖和基因驱动特性；S-III型具有代谢和甲基化驱动特性。最后，我们的研究提供了亚型指导的个性化治疗策略：免疫检查点阻断剂（ICB）、阿霉素、替匹法尼、AZ628和AZD6244适用于S-Ⅰ型；顺铂、喜树碱、罗可辛和A.443654适用于S-Ⅱ型；多西他赛、紫杉醇、长春瑞滨和BIBW2992适用于S-III型。
结论
我们为LUAD患者提供了一种新的分子分类策略，并揭示了三种基于药物基因组学的亚型，这揭示了潜在的亚型相关和患者特异性治疗策略。
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