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Background <p>The exon 19 deletion (19 Del) and the exon 21 L858R point mutation (21 L858R) are two main subtypes of <i>EGFR</i>-mutant lung adenocarcinoma (LUAD) with distinct response to targeted treatment and immunotherapy. Understanding the intratumor heterogeneity (ITH) of <i>EGFR</i>-mutant LUAD may explain the reason.</p> Methods <p>157 multi-region tumor samples and matched distant normal lung tissues from 29 treatment-naïve operable <i>EGFR</i>-mutant LUAD patients were collected to perform whole genome sequencing, panel sequencing and whole transcriptome sequencing. We aimed to comprehensively assess genomic and transcriptomic ITH between 19 Del and 21 L858R.</p> Results <p>The 21 L858R LUAD exhibited significantly higher copy number variation (CNV) ITH index (ITHi) compared to the 19 Del LUAD, but there was no significant difference in somatic single-nucleotide variant (SNV) ITHi between them. Meanwhile, 19 Del LUAD owned more clonal genetic alterations, while 21 L858R LUAD had more subclonal events. Both linear and branch evolution models existed in 19 Del and 21 L858R LUAD. Besides, 19 Del seemed to be more dominant for driving tumor development, while other driver mutations participated jointly with 21 L858R in tumor evolution. Moreover, 19 Del LUAD exhibited significantly higher immune score and checkpoint inhibition signature than 21 L858R. Additionally, it indicated that high-level TMB might be a favorable prognostic factor for <i>EGFR</i>-mutant LUAD.</p> Conclusions <p>Our study demonstrated diverse genomic heterogeneity and tumor immune microenvironment in <i>EGFR</i>-mutant LUAD, which might elaborate on potential explanations for different efficacy between 19 Del and 21 L858R and provide valuable hints to treatment strategy.</p>

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Diverse genomic and transcriptomic heterogeneity in EGFR-mutant lung adenocarcinoma between exon 19 del and exon 21 L858R

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月14日

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  • Yuwen Yang,
  • Sitan Qiao,
  • Dongchen Sun,
  • Zhonghan Zhang,
  • Yuanyuan Zhao,
  • Jianhua Zhan,
  • Yan Huang,
  • Hongyun Zhao,
  • Yunpeng Yang,
  • Kui Wu,
  • Xinlan Zhou,
  • Lanjun Zhang,
  • Hao Long,
  • Haoxian Yang,
  • Junye Wang,
  • Xin Wang,
  • Zhesheng Wen,
  • Lin Zhang,
  • Li Zhang,
  • Wenfeng Fang,
  • Xin Zhao,
  • Yaxiong Zhang

摘要

Background

The exon 19 deletion (19 Del) and the exon 21 L858R point mutation (21 L858R) are two main subtypes of EGFR-mutant lung adenocarcinoma (LUAD) with distinct response to targeted treatment and immunotherapy. Understanding the intratumor heterogeneity (ITH) of EGFR-mutant LUAD may explain the reason.

Methods

157 multi-region tumor samples and matched distant normal lung tissues from 29 treatment-naïve operable EGFR-mutant LUAD patients were collected to perform whole genome sequencing, panel sequencing and whole transcriptome sequencing. We aimed to comprehensively assess genomic and transcriptomic ITH between 19 Del and 21 L858R.

Results

The 21 L858R LUAD exhibited significantly higher copy number variation (CNV) ITH index (ITHi) compared to the 19 Del LUAD, but there was no significant difference in somatic single-nucleotide variant (SNV) ITHi between them. Meanwhile, 19 Del LUAD owned more clonal genetic alterations, while 21 L858R LUAD had more subclonal events. Both linear and branch evolution models existed in 19 Del and 21 L858R LUAD. Besides, 19 Del seemed to be more dominant for driving tumor development, while other driver mutations participated jointly with 21 L858R in tumor evolution. Moreover, 19 Del LUAD exhibited significantly higher immune score and checkpoint inhibition signature than 21 L858R. Additionally, it indicated that high-level TMB might be a favorable prognostic factor for EGFR-mutant LUAD.

Conclusions

Our study demonstrated diverse genomic heterogeneity and tumor immune microenvironment in EGFR-mutant LUAD, which might elaborate on potential explanations for different efficacy between 19 Del and 21 L858R and provide valuable hints to treatment strategy.