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Evolutionary proteogenomic landscape from pre-invasive to invasive lung adenocarcinoma

Yang Zhang,Fangqiu Fu,Qiao Zhang,Lingling Li,Hui Liu,Chaoqiang Deng,Qianqian Xue,Yue Zhao,Wenrui Sun,Han Han,Zhendong Gao,Chunmei Guo,Qiang Zheng,Hong Hu,Yihua Sun,Yuan Li,Chen Ding,Haiquan Chen

Summary Lung adenocarcinoma follows a stepwise progression from pre-invasive to invasive. However, there remains a knowledge gap regarding molecular events from pre-invasive to invasive. Here, we conduct a comprehensive proteogenomic analysis comprising whole-exon sequencing, RNA sequencing, and proteomic and phosphoproteomic profiling on 98 pre-invasive and 99 invasive lung adenocarcinomas. The deletion of chr4q12 contributes to the progression from pre-invasive to invasive adenocarcinoma by downregulating SPATA18, thus suppressing mitophagy and promoting cell invasion. Proteomics reveals diverse enriched pathways in normal lung tissues and pre-invasive and invasive adenocarcinoma. Proteomic analyses identify three proteomic subtypes, which represent different stages of tumor progression. We also illustrate the molecular characterization of four immune clusters, including endothelial cells, B cells, DCs, and immune depression subtype. In conclusion, this comprehensive proteogenomic study characterizes the molecular architecture and hallmarks from pre-invasive to invasive lung adenocarcinoma, guiding the way to a deeper understanding of the tumorigenesis and progression of this disease.