Cited by 174Lung Cancer Treatments and MutationsCancer Genomics and DiagnosticsLung Cancer Research Studies

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

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Nahar, Rahul, Zhai, Weiwei, Zhang, Tong, Takano, Angela, Khng, Alexis J., Lee, Yin Yeng, Liu, Xingliang, Lim, Chong Hee +19 more·2018·Nature Communications

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.

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  • Data from GEMMs point towards a context-dependent, conditional haplo-insufficient role for Atm loss in KrasG12D-driven lung tumorigenesis.

    “Thus, data from genetically engineered mouse models (GEMMs) point towards a context-dependent, conditional haplo-insufficient role for Atm loss in KrasG12D-driven lung tumorigenesis.”
  • Complete Atm inactivation is incompatible with cellular viability in the context of KrasG12D expression and bi-allelic Trp53 inactivation, suggesting that excessive DNA damage removes incipient cancer cells from the proliferative pool.

    “In contrast, complete Atm inactivation is incompatible with cellular viability in the context of KrasG12D expression and bi-allelic Trp53 inactivation, suggesting that excessive DNA damage in this context removes incipient cancer cells from the proliferative pool.”
  • Kras-driven lung carcinogenesis is accelerated by incomplete Atm loss in a p53 deficient setting.

    “Interestingly, Kras-driven lung carcinogenesis is accelerated by incomplete Atm loss in a p53 deficient setting”
  • In murine models, the impact of Atm inactivation on Kras-driven lung carcinogenesis is context-dependent and varies according to the functional status of p53.

    “In murine models the impact of Atm inactivation on Kras-driven lung carcinogenesis is context-dependent and varies according to the functional status of p53104.”

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Authors
Nahar, R., Zhai, W., Zhang, T., Takano, A., Khng, A. J., Lee, Y. Y., Liu, X., Lim, C. H., Koh, T. P. T., Aung, Z. W., Lim, T. K. H., Veeravalli, L., Yuan, J., Teo, A. S. M., Chan, C. X., Poh, H. M., Chua, I. M. L., Liew, A. A., Lau, D. P. X., Kwang, X. L., Toh, C. K., Lim, W.-T., Lim, B., Tam, W. L., Tan, E.-H., Hillmer, A. M., & Tan, D. S. W.
Affiliations
  • Genome Institute of Singapore (SG)
  • Nanyang Technological University (SG)
  • Singapore General Hospital (SG)
  • National Heart Centre Singapore (SG)
  • National Cancer Centre Singapore (SG)
  • University Hospital Cologne (DE)
Corresponding author
  • Hillmer, Axel M.
  • Tan, Daniel S. W.
Venue
Nature Communications
Published
2018-01-15
Volume
9
Issue
1
Pages
216-216
ISSN
2041-1723 (ISSN-L)
OpenAlex
W2783397995
Cited by
173
References
65
Citations by year
2026: 10 · 2025: 7 · 2024: 12 · 2023: 26 · 2022: 26 · 2021: 34 · 2020: 25 · 2019: 23 · 2018: 10
FWCI
17.32
Type
journal article
Language
en
Open access
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
  • National University of Singapore (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • DR-NTU (Nanyang Technological University) (submittedVersion, cc-by)
Funders
  • Francis Crick Institute (10112)
  • National Cancer Centre of Singapore
  • Nanomaterials Microdevices Research Center, Osaka Institute of Technology
  • Singapore General Hospital
  • Genome Institute of Singapore
  • Medical Research Council
  • National Medical Research Council (NMRC/TCR/007-NCC/2013)
  • Biomedical Research Council
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
Keywords
EGFR-mutant lung adenocarcinoma, Asian patients, whole-genome duplication, aneuploidy, clonal diversity, TP53 mutation, CDKN2A loss, RB1 loss, cell cycle dysregulation, gene amplification, gene deletion, EGFR tyrosine kinase inhibitor resistance, intratumoral heterogeneity, genomic instability, smoking-related lung cancer
MeSH terms
Exome Sequencing, Adenocarcinoma, Humans, Lung Neoplasms, Mutation, Drug Resistance, Neoplasm, Genetic Predisposition to Disease, Genomics, Asian People, Cell Line, Tumor, Protein Kinase Inhibitors, ErbB Receptors

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