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：

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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。