Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-017-02584-z
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Funding
- National Medical Research Council (Singapore) (NMRC) through the Translational and Clinical Research Program Non-Small Cell Lung Cancer: Targeting Cancer Stem Cell and Drug Resistance [NMRC/TCR/007-NCC/2013]
- Biomedical Research Council through the Strategic Positioning Fund Characterizing and Tracking Circulating Tumor Cells (CTCs) for Individualized Cancer Care
- Genome Institute of Singapore, Agency for Science Technology and Research
- NRMC clinician-scientist award [NMRC/CSA/007/2016]
- Trailblazer Foundation Ltd.
- Singapore Millenium Foundation
- National Cancer Centre Research Fund [NRFMP10111-10112]
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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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