Abstract

EGFR-mutant lung adenocarcinomas (LUAD) display diverse clinical trajectories and are characterized by rapid but short-lived responses to EGFR tyrosine kinase inhibitors (TKIs). Through sequencing of 79 spatially distinct regions from 16 early stage tumors, we show that despite low mutation burdens, EGFR-mutant Asian LUADs unexpectedly exhibit a complex genomic landscape with frequent and early whole-genome doubling, aneuploidy, and high clonal diversity. Multiple truncal alterations, including TP53 mutations and loss of CDKN2A and RB1, converge on cell cycle dysregulation, with late sector-specific high-amplitude amplifications and deletions that potentially beget drug resistant clones. We highlight the association between genomic architecture and clinical phenotypes, such as co-occurring truncal drivers and primary TKI resistance. Through comparative analysis with published smoking-related LUAD, we postulate that the high intra-tumor heterogeneity observed in Asian EGFR-mutant LUAD may be contributed by an early dominant driver, genomic instability, and low background mutation rates.

Details

Title
Elucidating the genomic architecture of Asian EGFR-mutant lung adenocarcinoma through multi-region exome sequencing
Author
Nahar, Rahul 1 ; Zhai, Weiwei 2 ; Zhang, Tong 3 ; Takano, Angela 4 ; Khng, Alexis J 1 ; Yin Yeng Lee 1 ; Liu, Xingliang 1 ; Lim, Chong Hee 5 ; Koh, Tina P T 5 ; Zaw Win Aung 6 ; Hon Lim, Tony Kiat 4 ; Veeravalli, Lavanya 7 ; Ju, Yuan 8 ; Teo, Audrey S M 1 ; Chan, Cheryl X 1 ; Poh, Huay Mei 1 ; Chua, Ivan M L 9 ; Liew, Audrey Ann 10 ; Xi Lau, Dawn Ping 11 ; Xue, Lin Kwang 11 ; Toh, Chee Keong 12 ; Wan-Teck, Lim 12 ; Lim, Bing 8   VIAFID ORCID Logo  ; Wai Leong Tam 8   VIAFID ORCID Logo  ; Eng-Huat Tan 12 ; Hillmer, Axel M 13   VIAFID ORCID Logo  ; Tan, Daniel S W 10 

 Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore, Singapore 
 Human Genetics, Genome Institute of Singapore, Singapore, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore, Singapore 
 Human Genetics, Genome Institute of Singapore, Singapore, Singapore 
 Department of Pathology, Singapore General Hospital, Singapore, Singapore 
 Department of Cardiothoracic Surgery, National Heart Centre Singapore, Singapore, Singapore 
 Division of Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore, Singapore 
 Research Pipeline Development, Genome Institute of Singapore, Singapore, Singapore 
 Cancer Stem Cell Biology, Genome Institute of Singapore, Singapore, Singapore 
 Next Generation Sequencing Platform, Genome Institute of Singapore, Singapore, Singapore 
10  Cancer Stem Cell Biology, Genome Institute of Singapore, Singapore, Singapore; Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore; Cancer Therapeutics Research Laboratory, Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore 
11  Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore; Cancer Therapeutics Research Laboratory, Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore 
12  Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore 
13  Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore, Singapore; Institute of Pathology, University Hospital Cologne, Cologne, Germany 
Pages
1-11
Publication year
2018
Publication date
Jan 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
1987709710
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.