Journal Article

Multi-omics analyses reveal biological and clinical insights in recurrent stage I non-small cell lung cancer

Song, Lujia, Wang, Zhoufeng, Li, Jingwei, Zhang, Li, Li, Weimin, Zhu, Guonian, Wang, Chengdi, Wu, Jiayang, Chen, Jingyao, Qiu, Rong, Chen, Xuelan, Li, Changshu

2025

Overview

Post-operative recurrence rates of stage I non-small cell lung cancer (NSCLC) range from 20% to 40%. Nonetheless, the molecular mechanisms underlying recurrence hitherto remain largely elusive. Here, we generate genomic, epigenomic and transcriptomic profiles of paired tumors and adjacent tissues from 122 stage I NSCLC patients, among which 57 patients develop recurrence after surgery during follow-up. Integrated analyses illustrate that the presence of predominantly solid or micropapillary histological subtypes, increased genomic instability, and APOBEC-related signature are associated with recurrence. Furthermore, TP53 missense mutation in DNA-binding domain could contribute to shorter time to recurrence. DNA hypomethylation is pronounced in recurrent NSCLC, and PRAME is the significantly hypomethylated and overexpressed gene in recurrent lung adenocarcinoma (LUAD). Mechanistically, hypomethylation at TEAD1 binding site facilitates the transcriptional activation of PRAME . Inhibition of PRAME restrains the tumor metastasis via downregulation of epithelial–mesenchymal transition-related genes. We also identify that enrichment of AT2 cells with higher copy number variation burden, exhausted CD8 + T cells and Macro_SPP1, along with the reduced interaction between AT2 and immune cells, is essential for the formation of ecosystem in recurrent LUAD. Finally, multi-omics clustering could stratify the NSCLC patients into 4 subclusters with varying recurrence risk and subcluster-specific therapeutic vulnerabilities. Collectively, this study constitutes a promising resource enabling insights into the biological mechanisms and clinical management for post-operative recurrence of stage I NSCLC. The molecular mechanisms underlying stage I non-small cell lung cancer (NSCLC) remain poorly understood. Here, the authors do multi-omics profiling of paired tumor and normal adjacent tissues from NSCLC patients, finding molecular processes and cell type proportions that are associated with recurrence.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45 / 45/23 / 45/91 / 49 / 631/67/1612/1350 / 631/67/68/2486 / 631/67/69 / 692/53 / Adenocarcinoma / Adenocarcinoma of Lung - genetics / Adenocarcinoma of Lung - pathology / Antigens, Neoplasm - genetics / Antigens, Neoplasm - metabolism / Binding sites / Biological analysis / Carcinoma, Non-Small-Cell Lung - genetics / Carcinoma, Non-Small-Cell Lung - pathology / Carcinoma, Non-Small-Cell Lung - surgery / CD8 antigen / Cell Line, Tumor / Clustering / Copy number / Deoxyribonucleic acid / DNA / DNA Methylation / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Epithelial-Mesenchymal Transition - genetics / Female / Gene Expression Profiling / Gene Expression Regulation, Neoplastic / Genomic instability / Genomics - methods / Humanities and Social Sciences / Humans / Immune system / Lung cancer / Lung Neoplasms - genetics / Lung Neoplasms - pathology / Lung Neoplasms - surgery / Lymphocytes / Lymphocytes T / Male / Metastases / Middle Aged / Missense mutation / Molecular modelling / multidisciplinary / Multiomics / Neoplasm Recurrence, Local - genetics / Neoplasm Recurrence, Local - pathology / Neoplasm Staging / Non-small cell lung carcinoma / p53 Protein / Patients / Science / Science (multidisciplinary) / Small cell lung carcinoma / Transcription activation / Transcription Factors - genetics / Transcription Factors - metabolism / Transcriptome / Transcriptomics / Tumor Suppressor Protein p53 - genetics / Tumors