1. Elucidating the genomic architecture of Asian EGFR-mutant lung adenocarcinoma through multi-region exome sequencing.
- Author
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Nahar R, Zhai W, Zhang T, Takano A, Khng AJ, Lee YY, Liu X, Lim CH, Koh TPT, Aung ZW, Lim TKH, Veeravalli L, Yuan J, Teo ASM, Chan CX, Poh HM, Chua IML, Liew AA, Lau DPX, Kwang XL, Toh CK, Lim WT, Lim B, Tam WL, Tan EH, Hillmer AM, and Tan DSW
- Subjects
- Adenocarcinoma ethnology, Adenocarcinoma pathology, Asian People genetics, Cell Line, Tumor, Drug Resistance, Neoplasm drug effects, Drug Resistance, Neoplasm genetics, Genetic Predisposition to Disease ethnology, Genetic Predisposition to Disease genetics, Humans, Lung Neoplasms ethnology, Lung Neoplasms pathology, Protein Kinase Inhibitors pharmacology, Adenocarcinoma genetics, ErbB Receptors genetics, Genomics methods, Lung Neoplasms genetics, Mutation, Exome Sequencing methods
- 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.
- Published
- 2018
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