Differences of molecular events driving pathological and radiological progression of lung adenocarcinomaResearch in context
Jun Shang,
He Jiang,
Yue Zhao,
Jinglei Lai,
Leming Shi,
Jingcheng Yang,
Haiquan Chen,
Yuanting Zheng
Affiliations
Jun Shang
State Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Sciences and Shanghai Cancer Center, Fudan University, Shanghai, China
He Jiang
State Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Sciences and Shanghai Cancer Center, Fudan University, Shanghai, China
Yue Zhao
Department of Thoracic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China; Institute of Thoracic Oncology, Fudan University, Shanghai, China
Jinglei Lai
Department of Thoracic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China; Institute of Thoracic Oncology, Fudan University, Shanghai, China
Leming Shi
State Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Sciences and Shanghai Cancer Center, Fudan University, Shanghai, China; Institute of Thoracic Oncology, Fudan University, Shanghai, China
Jingcheng Yang
State Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Sciences and Shanghai Cancer Center, Fudan University, Shanghai, China; Greater Bay Area Institute of Precision Medicine, 115 Jiaoxi Road, Guangzhou, China; Corresponding author. State Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Sciences and Shanghai Cancer Center, Fudan University, Shanghai, China.
Haiquan Chen
Department of Thoracic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China; Institute of Thoracic Oncology, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Corresponding author. Department of Thoracic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China.
Yuanting Zheng
State Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Sciences and Shanghai Cancer Center, Fudan University, Shanghai, China; Corresponding author. State Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Sciences and Shanghai Cancer Center, Fudan University, Shanghai, China.
Summary: Background: Ground-glass opacity (GGO)-like lung adenocarcinoma (LUAD) has been detected increasingly in the clinic and its inert property and superior survival indicate unique biological characteristics. However, we do not know much about them, which hampers identification of key reasons for the inert property of GGO-like LUAD. Methods: Using whole-exome sequencing and RNA sequencing, taking into account both radiological and pathological classifications of the same 197 patients concomitantly, we systematically interrogate genes driving the progression from GGO to solid nodule and potential reasons for the inertia of GGO. Using flow cytometry and IHC, we validated the abundance of immune cells and activity of cell proliferation. Findings: Identifying the differences between GGO and solid nodule, we found adenocarcinoma in situ/minimally invasive adenocarcinoma (AIS/MIA) and GGO-like LUAD exhibited lower TP53 mutation frequency and less active cell proliferation-related pathways than solid nodule in LUAD. Identifying the differences in GGO between AIS/MIA and LUAD, we noticed that EGFR mutation frequency and CNV load were significantly higher in LUAD than in AIS/MIA. Regulatory T cell was also higher in LUAD, while CD8+ T cell decreased from AIS/MIA to LUAD. Finally, we constructed a transcriptomic signature to quantify the development from GGO to solid nodule, which was an independent predictor of patients’ prognosis in 11 external LUAD datasets. Interpretation: Our results provide deeper insights into the indolent nature of GGO and provide a molecular basis for the treatment of GGO-like LUAD. Funding: This study was supported in part by the National Natural Science Foundation of China (32170657), the National Natural Science Foundation of China (82203037), and Shanghai Sailing Program (22YF1408900).
