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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.
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1 Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore, Singapore
2 Human Genetics, Genome Institute of Singapore, Singapore, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
3 Human Genetics, Genome Institute of Singapore, Singapore, Singapore
4 Department of Pathology, Singapore General Hospital, Singapore, Singapore
5 Department of Cardiothoracic Surgery, National Heart Centre Singapore, Singapore, Singapore
6 Division of Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore, Singapore
7 Research Pipeline Development, Genome Institute of Singapore, Singapore, Singapore
8 Cancer Stem Cell Biology, Genome Institute of Singapore, Singapore, Singapore
9 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