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

作者：Chengdi Wang, Jingwei Li, Jingyao Chen, Zhoufeng Wang, Guonian Zhu, Lujia Song, Jiayang Wu, Changshu Li, Rong Qiu, Xuelan Chen, Li Zhang, Weimin Li · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-024-55068-2 · 被引用次数：44 · 研究领域：Cancer Genomics and Diagnostics、RNA modifications and cancer、Lung Cancer Treatments and Mutations

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-spec...