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Elucidating the genomic architecture of Asian EGFR-mutant lung adenocarcinoma through multi-region exome sequencing.
Nature Communications ( IF 14.7 ) Pub Date : 2018-01-15 , DOI: 10.1038/s41467-017-02584-z
Rahul Nahar , Weiwei Zhai , Tong Zhang , Angela Takano , Alexis J. Khng , Yin Yeng Lee , Xingliang Liu , Chong Hee Lim , Tina P. T. Koh , Zaw Win Aung , Tony Kiat Hon Lim , Lavanya Veeravalli , Ju Yuan , Audrey S. M. Teo , Cheryl X. Chan , Huay Mei Poh , Ivan M. L. Chua , Audrey Ann Liew , Dawn Ping Xi Lau , Xue Lin Kwang , Chee Keong Toh , Wan-Teck Lim , Bing Lim , Wai Leong Tam , Eng-Huat Tan , Axel M. Hillmer , Daniel S. W. Tan

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.

中文翻译:

通过多区域外显子组测序阐明亚洲人EGFR突变型肺腺癌的基因组结构。

EGFR突变型肺腺癌(LUAD)表现出多种多样的临床轨迹,其特征是对EGFR酪氨酸激酶抑制剂(TKIs)的反应迅速但寿命短。通过对16个早期肿瘤的79个空间不同区域进行测序,我们显示,尽管突变负担很低,EGFR突变亚洲LUAD却意外地展现出复杂的基因组格局,具有频繁且早期的全基因组加倍,非整倍性和高克隆多样性。包括TP53突变和CDKN2A和RB1缺失在内的多种截短改变,都集中在细胞周期失调上,后期可能是特异性的高振幅扩增和缺失,可能会产生耐药性克隆。我们强调基因组架构和临床表型之间的关联,例如共同出现的截短驱动程序和原发性TKI抵抗力。
更新日期:2018-01-15
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