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Proteogenomics of Non-smoking Lung Cancer in East Asia Delineates Molecular Signatures of Pathogenesis and Progression

Yi-Ju Chen, Theodoros I. Roumeliotis, Ya-Hsuan Chang, Ching-Tai Chen, Chia-Li Hanmail,  Miao-Hsia Lin, Huei-Wen Chen, Gee-Chen Chang, Yih-Leong Chang, Chen-Tu Wu, Mong-Wei Lin, Min-Shu Hsieh, Yu-Tai Wang, Yet-Ran Chen, Inge Jonassen, Fatemeh Zamanzad Ghavidel, Ze-Shiang Lin, Kuen-Tyng Lin, Ching-Wen Chen, Pei-Yuan Sheu, Chen-Ting Hung, Ke-Chieh Huang, Hao-Chin Yang, Pei-Yi Lin, Ta-Chi Yen, Yi-Wei Lin, Jen-Hung Wang, Lovely Raghav, Chien-Yu Lin, Yan-Si Chen, Pei-Shan Wu, Chi-Ting Lai, Shao-Hsing Weng, Kang-Yi Su, Wei-Hung Chang, Pang-Yan Tsai, Ana I Robles, Henry Rodriguez, Yi-Jing Hsiao, Wen-Hsin Chang, Ting-Yi Sungmail, Jin-Shing Chenmail, Sung-Liang Yumail, Jyoti S Choudharymail, Hsuan-Yu Chenmail, Pan-Chyr Yangmail, Yu-Ju Chenmail.

 

Cell , Volume 182, Issue 1, Pages 1-262 (2020)

https://www.sciencedirect.com/science/article/pii/S0092867420307431

 

Summary

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.