Chen Yi-Ju, Roumeliotis Theodoros I, Chang Ya-Hsuan, Chen Ching-Tai, Han Chia-Li, Lin Miao-Hsia, Chen Huei-Wen, Chang Gee-Chen, Chang Yih-Leong, Wu Chen-Tu, Lin Mong-Wei, Hsieh Min-Shu, Wang Yu-Tai, Chen Yet-Ran, Jonassen Inge, Ghavidel Fatemeh Zamanzad, Lin Ze-Shiang, Lin Kuen-Tyng, Chen Ching-Wen, Sheu Pei-Yuan, Hung Chen-Ting, Huang Ke-Chieh, Yang Hao-Chin, Lin Pei-Yi, Yen Ta-Chi, Lin Yi-Wei, Wang Jen-Hung, Raghav Lovely, Lin Chien-Yu, Chen Yan-Si, Wu Pei-Shan, Lai Chi-Ting, Weng Shao-Hsing, Su Kang-Yi, Chang Wei-Hung, Tsai Pang-Yan, Robles Ana I, Rodriguez Henry, Hsiao Yi-Jing, Chang Wen-Hsin, Sung Ting-Yi, Chen Jin-Shing, Yu Sung-Liang, Choudhary Jyoti S, Chen Hsuan-Yu, Yang Pan-Chyr, Chen Yu-Ju
Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
Functional Proteomics Group, Chester Beatty Laboratories, The Institute of Cancer Research, London SW3 6JB, UK.
Cell. 2020 Jul 9;182(1):226-244.e17. doi: 10.1016/j.cell.2020.06.012.
Lung cancer in East Asia is characterized by a high percentage of never-smokers, early onset and predominant EGFR mutations. To illuminate the molecular phenotype of this demographically distinct disease, we performed a deep comprehensive proteogenomic study on a prospectively collected cohort in Taiwan, representing early stage, predominantly female, non-smoking lung adenocarcinoma. Integrated genomic, proteomic, and phosphoproteomic analysis delineated the demographically distinct molecular attributes and hallmarks of tumor progression. Mutational signature analysis revealed age- and gender-related mutagenesis mechanisms, characterized by high prevalence of APOBEC mutational signature in younger females and over-representation of environmental carcinogen-like mutational signatures in older females. A proteomics-informed classification distinguished the clinical characteristics of early stage patients with EGFR mutations. Furthermore, integrated protein network analysis revealed the cellular remodeling underpinning clinical trajectories and nominated candidate biomarkers for patient stratification and therapeutic intervention. This multi-omic molecular architecture may help develop strategies for management of early stage never-smoker lung adenocarcinoma.
东亚地区的肺癌具有不吸烟者比例高、发病早和EGFR突变占主导等特征。为了阐明这种在人口统计学上具有独特性的疾病的分子表型，我们对台湾一个前瞻性收集的队列进行了深入全面的蛋白质基因组学研究，该队列代表早期、以女性为主、不吸烟的肺腺癌。综合基因组、蛋白质组和磷酸蛋白质组分析描绘了在人口统计学上具有独特性的肿瘤进展分子特征和标志。突变特征分析揭示了与年龄和性别相关的诱变机制，其特征是年轻女性中APOBEC突变特征的高发生率以及老年女性中环境致癌物样突变特征的过度表现。基于蛋白质组学的分类区分了EGFR突变早期患者的临床特征。此外，综合蛋白质网络分析揭示了支撑临床病程的细胞重塑，并确定了用于患者分层和治疗干预的候选生物标志物。这种多组学分子结构可能有助于制定早期不吸烟肺腺癌的管理策略。
