Zhang Tongwu, Zhao Wei, Wirth Christopher, Díaz-Gay Marcos, Yin Jinhu, Cecati Monia, Marchegiani Francesca, Hoang Phuc H, Leduc Charles, Baine Marina K, Travis William D, Sholl Lynette M, Joubert Philippe, Sang Jian, McElderry John P, Klein Alyssa, Khandekar Azhar, Hartman Caleb, Rosenbaum Jennifer, Colón-Matos Frank J, Miraftab Mona, Saha Monjoy, Lee Olivia W, Jones Kristine M, Caporaso Neil E, Wong Maria Pik, Leung Kin Chung, Agnes Hsiung Chao, Chen Chih-Yi, Edell Eric S, Martínez Santamaría Jacobo, Schabath Matthew B, Yendamuri Sai S, Manczuk Marta, Lissowska Jolanta, Świątkowska Beata, Mukeria Anush, Shangina Oxana, Zaridze David, Holcatova Ivana, Mates Dana, Milosavljevic Sasa, Savic Milan, Bossé Yohan, Gould Rothberg Bonnie E, Christiani David C, Gaborieau Valerie, Brennan Paul, Liu Geoffrey, Hofman Paul, Homer Robert, Yang Soo-Ryum, Pesatori Angela C, Consonni Dario, Yang Lixing, Zhu Bin, Shi Jianxin, Brown Kevin, Rothman Nathaniel, Chanock Stephen J, Alexandrov Ludmil B, Choi Jiyeon, Cardelli Maurizio, Lan Qing, Nowak Martin A, Wedge David C, Landi Maria Teresa
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
Manchester Cancer Research Centre, The University of Manchester, Manchester, UK.
bioRxiv. 2025 Mar 16:2025.03.14.643063. doi: 10.1101/2025.03.14.643063.
Understanding lung cancer evolution can identify tools for intercepting its growth. In a landscape analysis of 1024 lung adenocarcinomas (LUAD) with deep whole-genome sequencing integrated with multiomic data, we identified 542 LUAD that displayed diverse clonal architecture. In this group, we observed an interplay between mobile elements, endogenous and exogenous mutational processes, distinct driver genes, and epidemiological features. Our results revealed divergent evolutionary trajectories based on tobacco smoking exposure, ancestry, and sex. LUAD from smokers showed an abundance of tobacco-related C:G>A:T driver mutations in plus short subclonal diversification. LUAD in never smokers showed early occurrence of copy number alterations and mutations associated with SBS5 and SBS40a mutational signatures. Tumors harboring mutations exhibited long latency, particularly in females of European-ancestry (EU_N). In EU_N, mutations preceded the occurrence of other driver genes, including and . Tumors from Asian never smokers showed a short clonal evolution and presented with heterogeneous repetitive patterns for the inferred mutational order. Importantly, we found that the mutational signature ID2 is a marker of a previously unrecognized mechanism for LUAD evolution. Tumors with ID2 showed short latency and high L1 retrotransposon activity linked to L1 promoter demethylation. These tumors exhibited an aggressive phenotype, characterized by increased genomic instability, elevated hypoxia scores, low burden of neoantigens, propensity to develop metastasis, and poor overall survival. Reactivated L1 retrotransposition-induced mutagenesis can contribute to the origin of the mutational signature ID2, including through the regulation of the transcriptional factor , a member of the KZFP family. The complex nature of LUAD evolution creates both challenges and opportunities for screening and treatment plans.
了解肺癌的演变过程有助于找到抑制其生长的方法。通过对1024例肺腺癌（LUAD）进行深度全基因组测序并整合多组学数据的全景分析，我们识别出542例呈现出不同克隆结构的LUAD。在这组病例中，我们观察到移动元件、内源性和外源性突变过程、不同的驱动基因以及流行病学特征之间的相互作用。我们的研究结果揭示了基于吸烟暴露、祖先和性别的不同进化轨迹。吸烟者的LUAD显示出大量与烟草相关的C:G>A:T驱动突变以及短片段亚克隆多样化。从不吸烟者的LUAD显示出早期出现的拷贝数改变以及与SBS5和SBS40a突变特征相关的突变。携带特定突变的肿瘤具有较长的潜伏期，尤其是在欧洲血统（EU_N）的女性中。在EU_N中，特定突变先于其他驱动基因出现，包括其他基因。亚洲从不吸烟者的肿瘤显示出较短的克隆进化过程，并呈现出推断突变顺序的异质重复模式。重要的是，我们发现突变特征ID2是LUAD进化中一种先前未被认识机制的标志物。具有ID2的肿瘤潜伏期短，L1反转录转座子活性高，与L1启动子去甲基化有关。这些肿瘤表现出侵袭性表型，其特征是基因组不稳定性增加、缺氧评分升高、新抗原负担低、发生转移的倾向以及总体生存率差。重新激活的L1反转录转座诱导的诱变作用可导致突变特征ID2的产生，包括通过调节转录因子（KZFP家族成员）。LUAD进化的复杂性为筛查和治疗方案带来了挑战和机遇。
