Elucidating the genomic architecture of Asian EGFR-mutant lung adenocarcinoma through multi-region exome sequencing

Rahul Nahar, Weiwei Zhai, Tong Zhang, Angela Takano, Alexis J. Khng, Yin Yeng Lee, Xingliang Liu, Chong Hee Lim, Tina P. T. Koh, Zaw Win Aung, Tony Kiat Hon Lim, Lavanya Veeravalli, Ju Yuan, Audrey S. M. Teo, Cheryl X. Chan, Huay Mei Poh, Ivan M. L. Chua, Audrey Ann Liew, Dawn Ping Xi Lau, Xue Lin Kwang, Chee Keong Toh, Wan-Teck Lim, Bing Lim, Wai Leong Tam, Eng-Huat Tan, Axel M. Hillmer () and Daniel S. W. Tan ()
Additional contact information
Rahul Nahar: Genome Institute of Singapore
Weiwei Zhai: Genome Institute of Singapore
Tong Zhang: Genome Institute of Singapore
Angela Takano: Singapore General Hospital
Alexis J. Khng: Genome Institute of Singapore
Yin Yeng Lee: Genome Institute of Singapore
Xingliang Liu: Genome Institute of Singapore
Chong Hee Lim: National Heart Centre Singapore
Tina P. T. Koh: National Heart Centre Singapore
Zaw Win Aung: National Cancer Centre Singapore
Tony Kiat Hon Lim: Singapore General Hospital
Lavanya Veeravalli: Genome Institute of Singapore
Ju Yuan: Genome Institute of Singapore
Audrey S. M. Teo: Genome Institute of Singapore
Cheryl X. Chan: Genome Institute of Singapore
Huay Mei Poh: Genome Institute of Singapore
Ivan M. L. Chua: Genome Institute of Singapore
Audrey Ann Liew: Genome Institute of Singapore
Dawn Ping Xi Lau: National Cancer Centre Singapore
Xue Lin Kwang: National Cancer Centre Singapore
Chee Keong Toh: National Cancer Centre Singapore
Wan-Teck Lim: National Cancer Centre Singapore
Bing Lim: Genome Institute of Singapore
Wai Leong Tam: Genome Institute of Singapore
Eng-Huat Tan: National Cancer Centre Singapore
Axel M. Hillmer: Genome Institute of Singapore
Daniel S. W. Tan: Genome Institute of Singapore

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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.

Date: 2018
References: Add references at CitEc
Citations: View citations in EconPapers (4)

Downloads: (external link)
https://www.nature.com/articles/s41467-017-02584-z Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-017-02584-z

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-017-02584-z

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().