Integrative analysis of lung adenocarcinoma across diverse ethnicities and exposures

Shankha Satpathy; Natalie M. Clark; Yi-Ju Chen; Noshad Hosseini; Ya-Hsuan Chang; Yi Hsiao; Jonathan T. Lei; Francesca Petralia; Jin-Shing Chen; Yifat Geffen; David I. Heiman; Indranil Paul; Hanbyul Cho; Michelle Hollenberg; Giacomo B. Marino; Kuen-Tyng Lin; Rahul Mannan; C. Jackson White; Joe Allen; Shayan C. Avanessian; M. Harry Kane; Ashley Wolfe; Miloni Kinarivala; Wenke Liu; Shankara Anand; Mong-Wei Lin; Moe Haines; Erik J. Bergstrom; Grant Hussey; Ginny Xiaohe Li; Deepak C. Mani; Hao Fang; Eric J. Jaehnig; Hasmik Keshishian; Brecca Miller; Kang-Yi Su; Yi-Jing Hsiao; Hsao-Hsun Hsu; Min-Shu Hsieh; Kuo-Hsuan Hsu; Alexi Monovoukas; Simone Gohsman; John R. Thorup; Yamei Deng; Yo Akiyama; Eden Deng; Eric Sheng-Wen Chen; Azra Krek; Rodrigo Espinoza; Weiping Ma; Daniel Charytonowicz; Robert Sebra; Jyun-Hong Lin; Yan-Si Chen; Yin-Chen Hsu; Ze-Shiang Lin; Kun-Chieh Chen; Chang-Wei Yeh; Yu-Tai Wang; Alexander J. Lazar; Mehdi Mesri; Eunkyung An; Xu Zhang; Karl R. Clauser; David Fenyö; Arul M. Chinnaiyan; Bing Zhang; Li Ding; Kelly Ruggles; Chelsea Newton; Hui Zhang; Pei Wang; Galen Hostetter; Gilbert S. Omenn; Chandan Kumar-Sinha; Mathangi Thiagarajan; Ramaswamy Govindan; Paul Paik; Abhijit Parolia; Qing K. Li; Avi Ma’ayan; Gad A. Getz; Saravana M. Dhanasekaran; Ana I. Robles; Gee-Chen Chang; Pan-Chyr Yang; Sung-Liang Yu; Hsuan-Yu Chen; Alexey I. Nesvizhskii; Steven A. Carr; D.R. Mani; Marcin P. Cieslik; Yu-Ju Chen; Michael A. Gillette; 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; 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; Clinical Proteomic Tumor Analysis Consortium

doi:10.1016/j.ccell.2025.07.011

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Integrative analysis of lung adenocarcinoma across diverse ethnicities and exposures

Journal article

Open access

Peer reviewed

Integrative analysis of lung adenocarcinoma across diverse ethnicities and exposures

Shankha Satpathy, Natalie M. Clark, Yi-Ju Chen, Noshad Hosseini, Ya-Hsuan Chang, Yi Hsiao, Jonathan T. Lei, Francesca Petralia, Jin-Shing Chen, Yifat Geffen, …

Cancer cell, Vol.43(9), pp.1731-1757.e17

09/08/2025

DOI: https://doi.org/10.1016/j.ccell.2025.07.011

PMID: 40749670

Abstract

biomarkers

CPTAC

genomics

ICPC

lung adenocarcinoma

mass spectrometry

never-smokers

proteogenomics

PTMs

smokers

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. [Display omitted] •Genomic fragmentation is a prognostic hallmark of LUAD•Carcinogens influence signaling in tumors and adjacent tissues•Proteomic clustering finds early-stage LUAD with advanced features•Integrating proteogenomics and screens nominates potential drugs for LUAD subtypes Satpathy et al. conducted a proteogenomic analysis of 406 lung adenocarcinoma tumors across diverse demographics revealing oncogenic mechanisms, the prognostic role of chromosomal instability, immune signaling patterns, sex-specific carcinogen effects, and early-stage tumors with “late-like” traits. These biomarkers and subtype-specific therapeutic atlas advance precision strategies for this lethal disease.

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Title: Integrative analysis of lung adenocarcinoma across diverse ethnicities and exposures
Creators: Shankha Satpathy - Broad Institute
Natalie M. Clark - Broad Institute
Yi-Ju Chen - Academia Sinica
Noshad Hosseini - University of Michigan
Ya-Hsuan Chang - National Health Research Institutes
Yi Hsiao - University of Michigan
Jonathan T. Lei - Baylor College of Medicine
Francesca Petralia - Icahn School of Medicine at Mount Sinai
Jin-Shing Chen - National Taiwan University Hospital
Yifat Geffen - Broad Institute
David I. Heiman - Broad Institute
Indranil Paul - Broad Institute
Hanbyul Cho - University of Michigan
Michelle Hollenberg - New York University
Giacomo B. Marino - Icahn School of Medicine at Mount Sinai
Kuen-Tyng Lin - Academia Sinica
Rahul Mannan - University of Michigan
C. Jackson White - Broad Institute
Joe Allen - Broad Institute
Shayan C. Avanessian - Broad Institute
M. Harry Kane - Broad Institute
Ashley Wolfe - University of Michigan
Miloni Kinarivala - University of Michigan
Wenke Liu - New York University
Shankara Anand - Broad Institute
Mong-Wei Lin - National Taiwan University Hospital
Moe Haines - Broad Institute
Erik J. Bergstrom - Broad Institute
Grant Hussey - New York University
Ginny Xiaohe Li - University of Michigan
Deepak C. Mani - Broad Institute
Hao Fang - Academia Sinica
Eric J. Jaehnig - Baylor College of Medicine
Hasmik Keshishian - Broad Institute
Brecca Miller - New York University
Kang-Yi Su - National Taiwan University
Yi-Jing Hsiao - University of Michigan
Hsao-Hsun Hsu - National Taiwan University Hospital
Min-Shu Hsieh - National Taiwan University Hospital
Kuo-Hsuan Hsu - Taichung Veterans General Hospital
Alexi Monovoukas - Broad Institute
Simone Gohsman - Broad Institute
John R. Thorup - Broad Institute
Yamei Deng - University of Michigan
Yo Akiyama - Broad Institute
Eden Deng - Icahn School of Medicine at Mount Sinai
Eric Sheng-Wen Chen - Academia Sinica
Azra Krek - Icahn School of Medicine at Mount Sinai
Rodrigo Espinoza - Academia Sinica
Weiping Ma - Icahn School of Medicine at Mount Sinai
Daniel Charytonowicz - Icahn School of Medicine at Mount Sinai
Robert Sebra - Icahn School of Medicine at Mount Sinai
Jyun-Hong Lin - Academia Sinica
Yan-Si Chen - Academia Sinica
Yin-Chen Hsu - National Taiwan University
Ze-Shiang Lin - Academia Sinica
Kun-Chieh Chen - Chung Shan Medical University Hospital
Chang-Wei Yeh - National Center for High-Performance Computing
Yu-Tai Wang - National Center for High-Performance Computing
Alexander J. Lazar - The University of Texas MD Anderson Cancer Center
Mehdi Mesri - Cancer Clinic
Eunkyung An - National Cancer Institute
Xu Zhang - National Cancer Institute
Karl R. Clauser - Broad Institute
David Fenyö - New York University
Arul M. Chinnaiyan - University of Michigan
Bing Zhang - Baylor College of Medicine
Li Ding - Washington University in St. Louis
Kelly Ruggles - New York University
Chelsea Newton - Van Andel Institute
Hui Zhang - Johns Hopkins University
Pei Wang - Icahn School of Medicine at Mount Sinai
Galen Hostetter - Van Andel Institute
Gilbert S. Omenn - University of Michigan
Chandan Kumar-Sinha - University of Michigan
Mathangi Thiagarajan - Frederick National Laboratory for Cancer Research
Ramaswamy Govindan - Washington University in St. Louis
Paul Paik - Memorial Sloan Kettering Cancer Center
Abhijit Parolia - University of Michigan
Qing K. Li - Johns Hopkins University
Avi Ma’ayan - Icahn School of Medicine at Mount Sinai
Gad A. Getz - Broad Institute
Saravana M. Dhanasekaran - University of Michigan
Ana I. Robles - National Cancer Institute
Gee-Chen Chang - Chung Shan Medical University Hospital
Pan-Chyr Yang - National Taiwan University
Sung-Liang Yu - National Taiwan University
Hsuan-Yu Chen - Academia Sinica
Alexey I. Nesvizhskii - University of Michigan
Steven A. Carr - Broad Institute
D.R. Mani - Broad Institute
Marcin P. Cieslik - University of Michigan
Yu-Ju Chen - Academia Sinica
Michael A. Gillette - Broad Institute
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
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
Clinical Proteomic Tumor Analysis Consortium
Publication Details: Cancer cell, Vol.43(9), pp.1731-1757.e17
Publisher: Elsevier Inc
Identifiers: 991006227529802656
Academic Unit: Surgery
Language: English
Resource Type: Journal article