Nahar, Rahul, Zhai, Weiwei ORCID: 0000-0001-7938-0226, Zhang, Tong ORCID: 0000-0002-2046-4502, Takano, Angela, Khng, Alexis J., Lee, Yin Yeng, Liu, Xingliang, Lim, Chong Hee, Koh, Tina P. T., Aung, Zaw Win, Lim, Tony Kiat Hon, Veeravalli, Lavanya, Yuan, Ju, Teo, Audrey S. M., Chan, Cheryl X., Poh, Huay Mei, Chua, Ivan M. L., Liew, Audrey Ann, Lau, Dawn Ping Xi, Kwang, Xue Lin, Toh, Chee Keong, Lim, Wan-Teck ORCID: 0000-0002-4655-0206, Lim, Bing, Tam, Wai Leong ORCID: 0000-0003-2365-5264, Tan, Eng-Huat, Hillmer, Axel M. and Tan, Daniel S. W. (2018). Elucidating the genomic architecture of Asian EGFR-mutant lung adenocarcinoma through multi-region exome sequencing. Nat. Commun., 9. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Nahar, RahulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhai, WeiweiUNSPECIFIEDorcid.org/0000-0001-7938-0226UNSPECIFIED
Zhang, TongUNSPECIFIEDorcid.org/0000-0002-2046-4502UNSPECIFIED
Takano, AngelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Khng, Alexis J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lee, Yin YengUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liu, XingliangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lim, Chong HeeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koh, Tina P. T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aung, Zaw WinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lim, Tony Kiat HonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Veeravalli, LavanyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yuan, JuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Teo, Audrey S. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chan, Cheryl X.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Poh, Huay MeiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chua, Ivan M. L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liew, Audrey AnnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lau, Dawn Ping XiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kwang, Xue LinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Toh, Chee KeongUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lim, Wan-TeckUNSPECIFIEDorcid.org/0000-0002-4655-0206UNSPECIFIED
Lim, BingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tam, Wai LeongUNSPECIFIEDorcid.org/0000-0003-2365-5264UNSPECIFIED
Tan, Eng-HuatUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hillmer, Axel M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tan, Daniel S. W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-198827
DOI: 10.1038/s41467-017-02584-z
Journal or Publication Title: Nat. Commun.
Volume: 9
Date: 2018
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2041-1723
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
COPY-NUMBER ALTERATION; MUTATIONAL PROCESSES; TUMOR HETEROGENEITY; CANCER GENOME; EVOLUTION; GROWTH; LANDSCAPE; DISCOVERY; AMPLIFICATION; INSTABILITYMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/19882

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