. 2020 Jul 9;182(1):226-244.e17.

doi: 10.1016/j.cell.2020.06.012.

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

Yi-Ju Chen¹, Theodoros I Roumeliotis², Ya-Hsuan Chang³, Ching-Tai Chen⁴, Chia-Li Han⁵, Miao-Hsia Lin¹, Huei-Wen Chen⁶, Gee-Chen Chang⁷, Yih-Leong Chang⁸, Chen-Tu Wu⁸, Mong-Wei Lin⁹, Min-Shu Hsieh⁸, Yu-Tai Wang¹⁰, Yet-Ran Chen¹¹, Inge Jonassen¹², Fatemeh Zamanzad Ghavidel¹², Ze-Shiang Lin¹³, Kuen-Tyng Lin¹, Ching-Wen Chen¹³, Pei-Yuan Sheu¹³, Chen-Ting Hung¹³, Ke-Chieh Huang¹, Hao-Chin Yang¹, Pei-Yi Lin¹, Ta-Chi Yen¹, Yi-Wei Lin⁹, Jen-Hung Wang⁴, Lovely Raghav¹⁴, Chien-Yu Lin³, Yan-Si Chen³, Pei-Shan Wu¹, Chi-Ting Lai¹, Shao-Hsing Weng¹, Kang-Yi Su¹⁵, Wei-Hung Chang¹¹, Pang-Yan Tsai¹¹, Ana I Robles¹⁶, Henry Rodriguez¹⁶, Yi-Jing Hsiao¹³, Wen-Hsin Chang¹⁷, Ting-Yi Sung¹⁸, Jin-Shing Chen¹⁹, Sung-Liang Yu²⁰, Jyoti S Choudhary²¹, Hsuan-Yu Chen²², Pan-Chyr Yang²³, Yu-Ju Chen²⁴

Affiliations

¹ Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
² Functional Proteomics Group, Chester Beatty Laboratories, The Institute of Cancer Research, London SW3 6JB, UK.
³ Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.
⁴ Institute of Information Science, Academia Sinica, Taipei, Taiwan.
⁵ Master Program in Clinical Pharmacogenomics and Pharmacoproteomics, College of Pharmacy, Taipei Medical University, Taipei, Taiwan. Electronic address: was@tmu.edu.tw.
⁶ Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
⁷ Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
⁸ Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
⁹ Division of Thoracic Surgery, Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
¹⁰ National Applied Research Laboratories, National Center for High-performance Computing, Hsinchu, Taiwan.
¹¹ Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan.
¹² Computational Biology Unit (CBU), Informatics Department, University of Bergen, Bergen, Norway.
¹³ Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
¹⁴ Institute of Statistical Science, Academia Sinica, Taipei, Taiwan; Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Bioinformatics Program, Taiwan International Graduate Program, Hsinchu, Taiwan.
¹⁵ Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan.
¹⁶ Office of Cancer Clinical Proteomics Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
¹⁷ Institute of Molecular Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
¹⁸ Institute of Information Science, Academia Sinica, Taipei, Taiwan. Electronic address: tsung@iis.sinica.edu.tw.
¹⁹ Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan. Electronic address: chenjs@ntu.edu.tw.
²⁰ Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan. Electronic address: slyu@ntu.edu.tw.
²¹ Functional Proteomics Group, Chester Beatty Laboratories, The Institute of Cancer Research, London SW3 6JB, UK. Electronic address: jyoti.choudhary@icr.ac.uk.
²² Institute of Statistical Science, Academia Sinica, Taipei, Taiwan; Ph.D. Program in Microbial Genomics, National Chung Hsing University, Taichung, Taiwan. Electronic address: hychen@stat.sinica.edu.tw.
²³ Department of Internal Medicine, National Taiwan University, Taipei, Taiwan; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. Electronic address: pcyang@ntu.edu.tw.
²⁴ Institute of Chemistry, Academia Sinica, Taipei, Taiwan; Department of Chemistry, National Taiwan University, Taipei, Taiwan. Electronic address: yujuchen@gate.sinica.edu.tw.

PMID: 32649875
DOI: 10.1016/j.cell.2020.06.012

Free article

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

Yi-Ju Chen et al. Cell. 2020.

Free article

. 2020 Jul 9;182(1):226-244.e17.

doi: 10.1016/j.cell.2020.06.012.

Authors

Affiliations

¹ Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
² Functional Proteomics Group, Chester Beatty Laboratories, The Institute of Cancer Research, London SW3 6JB, UK.
³ Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.
⁴ Institute of Information Science, Academia Sinica, Taipei, Taiwan.
⁵ Master Program in Clinical Pharmacogenomics and Pharmacoproteomics, College of Pharmacy, Taipei Medical University, Taipei, Taiwan. Electronic address: was@tmu.edu.tw.
⁶ Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
⁷ Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
⁸ Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
⁹ Division of Thoracic Surgery, Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
¹⁰ National Applied Research Laboratories, National Center for High-performance Computing, Hsinchu, Taiwan.
¹¹ Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan.
¹² Computational Biology Unit (CBU), Informatics Department, University of Bergen, Bergen, Norway.
¹³ Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
¹⁴ Institute of Statistical Science, Academia Sinica, Taipei, Taiwan; Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Bioinformatics Program, Taiwan International Graduate Program, Hsinchu, Taiwan.
¹⁵ Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan.
¹⁶ Office of Cancer Clinical Proteomics Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
¹⁷ Institute of Molecular Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
¹⁸ Institute of Information Science, Academia Sinica, Taipei, Taiwan. Electronic address: tsung@iis.sinica.edu.tw.
¹⁹ Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan. Electronic address: chenjs@ntu.edu.tw.
²⁰ Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan. Electronic address: slyu@ntu.edu.tw.
²¹ Functional Proteomics Group, Chester Beatty Laboratories, The Institute of Cancer Research, London SW3 6JB, UK. Electronic address: jyoti.choudhary@icr.ac.uk.
²² Institute of Statistical Science, Academia Sinica, Taipei, Taiwan; Ph.D. Program in Microbial Genomics, National Chung Hsing University, Taichung, Taiwan. Electronic address: hychen@stat.sinica.edu.tw.
²³ Department of Internal Medicine, National Taiwan University, Taipei, Taiwan; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. Electronic address: pcyang@ntu.edu.tw.
²⁴ Institute of Chemistry, Academia Sinica, Taipei, Taiwan; Department of Chemistry, National Taiwan University, Taipei, Taiwan. Electronic address: yujuchen@gate.sinica.edu.tw.

PMID: 32649875
DOI: 10.1016/j.cell.2020.06.012

Abstract

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.

Keywords: APOBEC signature; MMP; carcinogen signature; genomics; lung cancer; non-smoker; phosphoproteomics; proteogenomics; proteomics; subtyping.

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Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

Comment in

Across the Globe: Proteogenomic Landscapes of Lung Cancer.
Yanovich-Arad G, Geiger T. Yanovich-Arad G, et al. Cell. 2020 Jul 9;182(1):9-11. doi: 10.1016/j.cell.2020.06.016. Cell. 2020. PMID: 32649881
Proteogenomics reveals molecular subtypes.
Sidaway P. Sidaway P. Nat Rev Clin Oncol. 2020 Sep;17(9):519. doi: 10.1038/s41571-020-0419-6. Nat Rev Clin Oncol. 2020. PMID: 32719419 No abstract available.
Proteogenomics Clarifies Picture of Lung Cancer.
[No authors listed] [No authors listed] Cancer Discov. 2020 Oct;10(10):OF3. doi: 10.1158/2159-8290.CD-NB2020-071. Epub 2020 Aug 5. Cancer Discov. 2020. PMID: 32759305

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

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Grants and funding

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Medical

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