Integrative analysis of lung adenocarcinoma across diverse ethnicities and exposures

Shankha Satpathy¹, Natalie M Clark², Yi-Ju Chen³, Noshad Hosseini⁴, Ya-Hsuan Chang⁵, Yi Hsiao⁴, Jonathan T Lei⁶, Francesca Petralia⁷, Jin-Shing Chen⁸, Yifat Geffen⁹, David I Heiman², Indranil Paul², Hanbyul Cho⁴, Michelle Hollenberg¹⁰, Giacomo B Marino⁷, Kuen-Tyng Lin³, Rahul Mannan⁴, C Jackson White², Joe Allen², Shayan C Avanessian², M Harry Kane², Ashley Wolfe⁴, Miloni Kinarivala⁴, Wenke Liu¹⁰, Shankara Anand², Mong-Wei Lin⁸, Moe Haines², Erik J Bergstrom², Grant Hussey¹⁰, Ginny Xiaohe Li⁴, Deepak C Mani², Hao Fang³, Eric J Jaehnig⁶, Hasmik Keshishian², Brecca Miller¹⁰, Kang-Yi Su¹¹, Yi-Jing Hsiao³, Hsao-Hsun Hsu⁸, Min-Shu Hsieh⁸, Kuo-Hsuan Hsu¹², Alexi Monovoukas², Simone Gohsman², John R Thorup², Yamei Deng⁴, Yo Akiyama², Eden Deng⁷, Eric Sheng-Wen Chen³, Azra Krek⁷, Rodrigo Espinoza³, Weiping Ma⁷, Daniel Charytonowicz⁷, Robert Sebra⁷, Jyun-Hong Lin³, Yan-Si Chen³, Yin-Chen Hsu¹¹, Ze-Shiang Lin³, Kun-Chieh Chen¹³, Chang-Wei Yeh¹⁴, Yu-Tai Wang¹⁴, Alexander J Lazar¹⁵, Mehdi Mesri¹⁶, Eunkyung An¹⁶, Xu Zhang¹⁶, Karl R Clauser², David Fenyö¹⁰, Arul M Chinnaiyan⁴, Bing Zhang⁶, Li Ding¹⁷, Kelly Ruggles¹⁰, Chelsea Newton¹⁸, Hui Zhang¹⁹, Pei Wang⁷, Galen Hostetter¹⁸, Gilbert S Omenn⁴, Chandan Kumar-Sinha⁴, Mathangi Thiagarajan²⁰, Ramaswamy Govindan¹⁷, Paul Paik²¹, Abhijit Parolia⁴, Qing K Li²², Avi Ma'ayan⁷, Gad A Getz⁹, Saravana M Dhanasekaran⁴, Ana I Robles¹⁶, Gee-Chen Chang¹³, Pan-Chyr Yang¹¹, Sung-Liang Yu²³, Hsuan-Yu Chen²⁴, Alexey I Nesvizhskii⁴, Steven A Carr², D R Mani²⁵, Marcin P Cieslik²⁶, Yu-Ju Chen²⁷, Michael A Gillette²⁸; Taiwan Cancer Moonshot Program; Clinical Proteomic Tumor Analysis Consortium

Collaborators, Affiliations

Collaborators

Taiwan Cancer Moonshot Program:
Chao-Wen Lu, Cheng-Hsiang Chu, Chi-Ya Shen, Chia-Li Han, Chien-Chia Lin, Chien-Yu Lin, Ching-Wen Chen, Chung-Hsien Lin, Hsiang-En Hsu, Hsing-Jui Tsai, Jia-Jun Wu, Jing-Wei Lin, Juani Waniwan, Ki-Hok Liao, Pei-Hsing Chen, Pei-Rong Huang, Sin-Ming Huang, Tai-Ching Lin, Wan-Chun Lai, Wei-Tzu Chiu, Xu-Heng Chiang, Ya-Ling Chang, Yan-Ming Chen, Yi-Ling Chen, Yi-Wen Wang, Yi-Wei Lin, Yu-Cheng Chang, Yu-Ting Huang, Yuju Lien, Zhe-Rong Zheng
Clinical Proteomic Tumor Analysis Consortium:
Abdul Samad Hashimi, Adrij Mohan, Akhilesh Pandey, Alexander Pilozzi, Alex Webster, Amanda G Paulovich, Aniket Dagar, Andrew K Godwin, Barbara Pruetz, Bart O Williams, Brian J Druker, Daniel C Rohrer, Daniel W Chan, Danail Petrov, David Chesla, Diwakar Davaar, Elizabeth Duffy, George D Wilson, Grace Zhao, Iga Kołodziejczak, Jan Lubinski, Jasmine Huang, Jason Hafron, Jeffrey W Tyner, John Koomen, Kakhaber Zaalishvili, Karen A Ketchum, Maciej Wiznerowicz, Marcin J Domagalski, Meenakshi Anurag, Melissa Borucki, Nathan J Edwards, Negin Vatanian, Pamela Grady, Paul D Piehowski, Popovici Bogdan, Qin Li, Rafael Fonseca, Rashna Madan, Ratna R Thangudu, Reese Crispen, Ronald Matteotti, Ross Bremner, Sandra Cerda, Sandra L Cottingham, Shirley Tsang, Shuang Cai, Tao Liu, Thomas Bauer, William W Maggio, Xiaojun Jing, Yuping Zhang, Yvonne Shutack, Zoran Andric

Affiliations

¹ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: shankha@broadinstitute.org.
² Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Academia Sinica, Taipei, TW, Taiwan.
⁴ University of Michigan, Ann Arbor, MI 48109, USA.
⁵ National Health Research Institutes, Miaoli County, TW, Taiwan.
⁶ Baylor College of Medicine, Houston, TX 77030, USA.
⁷ Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁸ National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, TW, Taiwan.
⁹ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Massachusetts General Hospital, Boston, MA 02114, USA.
¹⁰ NYU Grossman School of Medicine, New York, NY 10016, USA.
¹¹ National Taiwan University, Taipei, TW, Taiwan.
¹² Taichung Veterans General Hospital, Taichung, TW, Taiwan.
¹³ Chung Shan Medical University Hospital, Taichung, TW, Taiwan.
¹⁴ National Center for High-performance Computing, National Applied Research Laboratories, Hsinchu, TW, Taiwan.
¹⁵ The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁶ Office of Cancer Clinical Proteomics Research, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD 20850, USA.
¹⁷ Washington University in St. Louis, St. Louis, MO 63110, USA.
¹⁸ Van Andel Research Institute, Grand Rapids, MI 49503, USA.
¹⁹ Johns Hopkins University, Baltimore, MD 21231, USA.
²⁰ Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
²¹ Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA.
²² Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
²³ National Taiwan University, Taipei, TW, Taiwan. Electronic address: slyu@ntu.edu.tw.
²⁴ Academia Sinica, Taipei, TW, Taiwan; National Chung Hsing University, Taichung, TW, Taiwan. Electronic address: hychen@stat.sinica.edu.tw.
²⁵ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: manidr@broadinstitute.org.
²⁶ University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: mcieslik@med.umich.edu.
²⁷ Academia Sinica, Taipei, TW, Taiwan; National Taiwan University, Taipei, TW, Taiwan. Electronic address: yujuchen@gate.sinica.edu.tw.
²⁸ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: gillette@broadinstitute.org.

PMID: 40749670
PMCID: PMC12393171 (available on 2026-07-31)
DOI: 10.1016/j.ccell.2025.07.011

Integrative analysis of lung adenocarcinoma across diverse ethnicities and exposures

Shankha Satpathy et al. Cancer Cell. 2025.

. 2025 Sep 8;43(9):1731-1757.e17.

doi: 10.1016/j.ccell.2025.07.011. Epub 2025 Jul 31.

Authors

Collaborators

Taiwan Cancer Moonshot Program:
Chao-Wen Lu, Cheng-Hsiang Chu, Chi-Ya Shen, Chia-Li Han, Chien-Chia Lin, Chien-Yu Lin, Ching-Wen Chen, Chung-Hsien Lin, Hsiang-En Hsu, Hsing-Jui Tsai, Jia-Jun Wu, Jing-Wei Lin, Juani Waniwan, Ki-Hok Liao, Pei-Hsing Chen, Pei-Rong Huang, Sin-Ming Huang, Tai-Ching Lin, Wan-Chun Lai, Wei-Tzu Chiu, Xu-Heng Chiang, Ya-Ling Chang, Yan-Ming Chen, Yi-Ling Chen, Yi-Wen Wang, Yi-Wei Lin, Yu-Cheng Chang, Yu-Ting Huang, Yuju Lien, Zhe-Rong Zheng
Clinical Proteomic Tumor Analysis Consortium:
Abdul Samad Hashimi, Adrij Mohan, Akhilesh Pandey, Alexander Pilozzi, Alex Webster, Amanda G Paulovich, Aniket Dagar, Andrew K Godwin, Barbara Pruetz, Bart O Williams, Brian J Druker, Daniel C Rohrer, Daniel W Chan, Danail Petrov, David Chesla, Diwakar Davaar, Elizabeth Duffy, George D Wilson, Grace Zhao, Iga Kołodziejczak, Jan Lubinski, Jasmine Huang, Jason Hafron, Jeffrey W Tyner, John Koomen, Kakhaber Zaalishvili, Karen A Ketchum, Maciej Wiznerowicz, Marcin J Domagalski, Meenakshi Anurag, Melissa Borucki, Nathan J Edwards, Negin Vatanian, Pamela Grady, Paul D Piehowski, Popovici Bogdan, Qin Li, Rafael Fonseca, Rashna Madan, Ratna R Thangudu, Reese Crispen, Ronald Matteotti, Ross Bremner, Sandra Cerda, Sandra L Cottingham, Shirley Tsang, Shuang Cai, Tao Liu, Thomas Bauer, William W Maggio, Xiaojun Jing, Yuping Zhang, Yvonne Shutack, Zoran Andric

Affiliations

¹ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: shankha@broadinstitute.org.
² Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Academia Sinica, Taipei, TW, Taiwan.
⁴ University of Michigan, Ann Arbor, MI 48109, USA.
⁵ National Health Research Institutes, Miaoli County, TW, Taiwan.
⁶ Baylor College of Medicine, Houston, TX 77030, USA.
⁷ Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁸ National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, TW, Taiwan.
⁹ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Massachusetts General Hospital, Boston, MA 02114, USA.
¹⁰ NYU Grossman School of Medicine, New York, NY 10016, USA.
¹¹ National Taiwan University, Taipei, TW, Taiwan.
¹² Taichung Veterans General Hospital, Taichung, TW, Taiwan.
¹³ Chung Shan Medical University Hospital, Taichung, TW, Taiwan.
¹⁴ National Center for High-performance Computing, National Applied Research Laboratories, Hsinchu, TW, Taiwan.
¹⁵ The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁶ Office of Cancer Clinical Proteomics Research, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD 20850, USA.
¹⁷ Washington University in St. Louis, St. Louis, MO 63110, USA.
¹⁸ Van Andel Research Institute, Grand Rapids, MI 49503, USA.
¹⁹ Johns Hopkins University, Baltimore, MD 21231, USA.
²⁰ Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
²¹ Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA.
²² Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
²³ National Taiwan University, Taipei, TW, Taiwan. Electronic address: slyu@ntu.edu.tw.
²⁴ Academia Sinica, Taipei, TW, Taiwan; National Chung Hsing University, Taichung, TW, Taiwan. Electronic address: hychen@stat.sinica.edu.tw.
²⁵ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: manidr@broadinstitute.org.
²⁶ University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: mcieslik@med.umich.edu.
²⁷ Academia Sinica, Taipei, TW, Taiwan; National Taiwan University, Taipei, TW, Taiwan. Electronic address: yujuchen@gate.sinica.edu.tw.
²⁸ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: gillette@broadinstitute.org.

PMID: 40749670
PMCID: PMC12393171 (available on 2026-07-31)
DOI: 10.1016/j.ccell.2025.07.011

Abstract

Lung adenocarcinomas (LUAD) are a pressing global health problem with enduring lethality and rapidly shifting epidemiology. Proteogenomic studies integrating proteomics and post-translational modifications with genomics can identify clinical strata and oncogenic mechanisms, but have been underpowered to examine effects of ethnicity, smoking and environmental exposures, or sex on this heterogeneous disease. This comprehensive proteogenomic analysis of LUAD tumors and matched normal adjacent tissues from 406 patients across diverse geographic and demographic backgrounds explores the impact of understudied driver mutations, prognostic role of chromosomal instability, patterns of immune signaling, differential and sex-specific effects of endogenous mutagens and environmental carcinogens, and pathobiology of early-stage tumors with "late-like" characteristics. Candidate protein biomarkers are proposed for unstable tumors with highly fragmented genomes and for carcinogen exposures, and a LUAD subtype-specific atlas of therapeutic vulnerabilities is presented. These observations and the associated data resource advance the objective of precision management strategies for this devastating disease.

Keywords: CPTAC; ICPC; PTMs; biomarkers; genomics; lung adenocarcinoma; mass spectrometry; never-smokers; proteogenomics; smokers.

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Conflict of interest statement

Declaration of interests Grants or contracts (institutional research) for P.P. from EMD Serono, Bicara, Novartis and Advisory Board/Consulting for Novartis, Mirati, Janssen, EMD Serono, Takeda, Bicara, AstraZeneca. S.S. is currently employed by AstraZeneca. This work was conducted while S.S. was employed at the Broad Institute and AstraZeneca has no role in this study. The rest of the authors have no competing interests.

References

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Integrative analysis of lung adenocarcinoma across diverse ethnicities and exposures

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Integrative analysis of lung adenocarcinoma across diverse ethnicities and exposures

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Abstract

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