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

作者：Nahar Rahul; Zhai Weiwei; Zhang Tong; 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; Lim Bing; Tam Wai Leong; Tan Eng Huat; Hillmer Axel M^*; Tan Daniel S W^*

来源：Nature Communications, 2018, 9(1): 216.

DOI：10.1038/s41467-017-02584-z

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.

• 出版日期2018-1-15