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 Han; 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 Sung; Jin Shing Chen; Sung Liang Yu; Jyoti S. Choudhary; Hsuan Yu Chen; Pan Chyr Yang; Yu Ju Chen

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 Chen, Theodoros I. Roumeliotis, Ya Hsuan Chang, Ching Tai Chen, Chia Li Han, 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 SheuChen 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 Sung, Jin Shing Chen, Sung Liang Yu, Jyoti S. Choudhary, Hsuan Yu Chen, Pan Chyr Yang, Yu Ju Chen

Research output: Contribution to journal › Article › peer-review

267 Citations (Scopus)

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.

Original language	English
Pages (from-to)	226-244.e17
Journal	Cell
Volume	182
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2020.06.012
Publication status	Published - Jul 9 2020

Keywords

APOBEC signature
carcinogen signature
genomics
lung cancer
MMP
non-smoker
phosphoproteomics
proteogenomics
proteomics
subtyping

ASJC Scopus subject areas

General Biochemistry,Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2020.06.012

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Chen, Y. J., Roumeliotis, T. I., Chang, Y. H., Chen, C. T., Han, C. L., Lin, M. H., Chen, H. W., Chang, G. C., Chang, Y. L., Wu, C. T., Lin, M. W., Hsieh, M. S., Wang, Y. T., Chen, Y. R., Jonassen, I., Ghavidel, F. Z., Lin, Z. S., Lin, K. T., Chen, C. W., ... Chen, Y. J. (2020). Proteogenomics of Non-smoking Lung Cancer in East Asia Delineates Molecular Signatures of Pathogenesis and Progression. Cell, 182(1), 226-244.e17. https://doi.org/10.1016/j.cell.2020.06.012

Chen, YJ, Roumeliotis, TI, Chang, YH, Chen, CT, Han, CL, Lin, MH, Chen, HW, Chang, GC, Chang, YL, Wu, CT, Lin, MW, Hsieh, MS, Wang, YT, Chen, YR, Jonassen, I, Ghavidel, FZ, Lin, ZS, Lin, KT, Chen, CW, Sheu, PY, Hung, CT, Huang, KC, Yang, HC, Lin, PY, Yen, TC, Lin, YW, Wang, JH, Raghav, L, Lin, CY, Chen, YS, Wu, PS, Lai, CT, Weng, SH, Su, KY, Chang, WH, Tsai, PY, Robles, AI, Rodriguez, H, Hsiao, YJ, Chang, WH, Sung, TY, Chen, JS, Yu, SL, Choudhary, JS, Chen, HY, Yang, PC & Chen, YJ 2020, 'Proteogenomics of Non-smoking Lung Cancer in East Asia Delineates Molecular Signatures of Pathogenesis and Progression', Cell, vol. 182, no. 1, pp. 226-244.e17. https://doi.org/10.1016/j.cell.2020.06.012

@article{a7b7f7e433394274b9b4fa491e7863e7,

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

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, carcinogen signature, genomics, lung cancer, MMP, non-smoker, phosphoproteomics, proteogenomics, proteomics, subtyping",

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

note = "Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = jul,

day = "9",

doi = "10.1016/j.cell.2020.06.012",

language = "English",

volume = "182",

pages = "226--244.e17",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "1",

}

TY - JOUR

T1 - Proteogenomics of Non-smoking Lung Cancer in East Asia Delineates Molecular Signatures of Pathogenesis and Progression

AU - Chen, Yi Ju

AU - Roumeliotis, Theodoros I.

AU - Chang, Ya Hsuan

AU - Chen, Ching Tai

AU - Han, Chia Li

AU - Lin, Miao Hsia

AU - Chen, Huei Wen

AU - Chang, Gee Chen

AU - Chang, Yih Leong

AU - Wu, Chen Tu

AU - Lin, Mong Wei

AU - Hsieh, Min Shu

AU - Wang, Yu Tai

AU - Chen, Yet Ran

AU - Jonassen, Inge

AU - Ghavidel, Fatemeh Zamanzad

AU - Lin, Ze Shiang

AU - Lin, Kuen Tyng

AU - Chen, Ching Wen

AU - Sheu, Pei Yuan

AU - Hung, Chen Ting

AU - Huang, Ke Chieh

AU - Yang, Hao Chin

AU - Lin, Pei Yi

AU - Yen, Ta Chi

AU - Lin, Yi Wei

AU - Wang, Jen Hung

AU - Raghav, Lovely

AU - Lin, Chien Yu

AU - Chen, Yan Si

AU - Wu, Pei Shan

AU - Lai, Chi Ting

AU - Weng, Shao Hsing

AU - Su, Kang Yi

AU - Chang, Wei Hung

AU - Tsai, Pang Yan

AU - Robles, Ana I.

AU - Rodriguez, Henry

AU - Hsiao, Yi Jing

AU - Chang, Wen Hsin

AU - Sung, Ting Yi

AU - Chen, Jin Shing

AU - Yu, Sung Liang

AU - Choudhary, Jyoti S.

AU - Chen, Hsuan Yu

AU - Yang, Pan Chyr

AU - Chen, Yu Ju

PY - 2020/7/9

Y1 - 2020/7/9

N2 - 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.

AB - 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.

KW - APOBEC signature

KW - carcinogen signature

KW - genomics

KW - lung cancer

KW - MMP

KW - non-smoker

KW - phosphoproteomics

KW - proteogenomics

KW - proteomics

KW - subtyping

UR - https://www.scopus.com/pages/publications/85087414083

UR - https://www.scopus.com/inward/citedby.url?scp=85087414083&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2020.06.012

DO - 10.1016/j.cell.2020.06.012

M3 - Article

C2 - 32649875

AN - SCOPUS:85087414083

SN - 0092-8674

VL - 182

SP - 226-244.e17

JO - Cell

JF - Cell

IS - 1

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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